Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

November 27, 2019

The Honorable Seema Verma
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
200 Independence Avenue, SW
Washington, DC 20201

RE: CAG-00450R — Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

Dear Administrator Verma:

The undersigned cancer patient, provider, and research organizations are writing to comment on the proposed decision memo for Next Generation Sequencing (NGS) for Medicare beneficiaries. We are pleased that the Centers for Medicare & Medicaid Services (CMS) heard the concerns of patients and providers regarding limitations on germline testing in the initial coverage decision and has proposed revisions to the previously defined standards.

We are aware that many other cancer organizations have offered comments on the proposed decision memo, in some cases providing cancer site-specific data about somatic and germline testing and its benefits. We support those efforts and offer our own collective views, reflecting the needs of all cancer patients. In addition, we understand the challenge that CMS faces, to ensure access to appropriate NGS testing that will provide patients and providers information to guide diagnosis, treatment, and monitoring of treatment while at the same time protecting Medicare for future beneficiaries.

• Permit Medicare Administrative Contractors (MACs) to develop local coverage determinations (LCDs) for NGS-based germline testing of patients with suspected hereditary cancer, including breast and ovarian cancer.

The proposed decision memo would establish a national coverage standard for NGS for ovarian and breast cancer patients when the test using NGS is Food and Drug Administration (FDA)-approved or cleared. Establishing a national standard of this sort would have the unfortunate effect of denying germline testing for those with breast and ovarian cancer, because there are currently no NGS-based germline tests that are FDA-approved or cleared. Further, under this national coverage standard, Medicare Administrative Contractors (MACs) would not be permitted to develop coverage policies for NGS-based germline tests for breast and ovarian cancer.

We recommend instead that MACs be given the authority to determine coverage for NGS for all patients with a cancer diagnosis, including those with breast or ovarian cancer.

• Permit NGS tests when reasonable and necessary and without a limit of one test per diagnosis.

The proposed decision memo would place limits on the frequency of NGS testing. Those patients who have previously received NGS-based somatic tests would not be permitted to receive germline testing, and there would be limits on the frequency of somatic testing. We recommend instead that the proposed decision memo permit testing as determined appropriate. A patient who has received somatic NGS testing might still benefit from germline testing, for information to guide treatment decisions and management of disease. Additional NGS somatic testing may also provide important information about changes in the patient’s disease and necessary adjustments to treatment. Additional tests may provide information regarding the transformation of some cancers and accompanying treatment changes.

• Revise the language of the coverage memo to ensure that Medicare beneficiaries with hematological malignancies have access to NGS tests.

The language of the initial coverage memo referenced the use of NGS technology in patients with “recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer.” This system of staging is not appropriate for hematological malignancies, and as a result coverage for somatic or germline testing for these beneficiaries is unclear. We urge CMS to clarify the language of the decision memo so that there is no question about the utilization of NGS technology for beneficiaries with hematological malignancies.

We appreciate the willingness of CMS to consider and respond to input from cancer stakeholders regarding coverage of NGS technology. With the modifications of the coverage decision memo recommended above and by others in their comments to the agency, we believe that CMS can achieve an appropriate coverage standard for somatic and germline testing.

Sincerely,

Cancer Leadership Council

American Society of Clinical Oncology
Association for Molecular Pathology
CancerCare
Children’s Cancer Cause
College of American Pathologists
International Myeloma Foundation
LUNGevity Foundation
Lymphoma Research Foundation
National Coalition for Cancer Survivorship
Ovarian Cancer Research Alliance
Prevent Cancer Foundation
Sarcoma Foundation of America
Susan G. Komen

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November 28, 2019

Seema Verma, Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
200 Independence Avenue, SW
Washington, DC 20201

Dear Administrator Verma:

The undersigned organizations represent a diverse and broad community of patient advocates and providers committed to ensuring cancer patients have access to clinically appropriate, high-quality cancer care. The patients we represent and treat are benefitting from advances in the understanding of the genomic causes of cancer, both in increased access to targeted therapeutics and in innovative diagnostics that improve their ability to prevent cancer and monitor disease progression. This letter is in regard to the Centers for Medicare and Medicaid Services (CMS) reconsideration of the National Coverage Determination (NCD) on Next Generation Sequencing (NGS) for Medicare beneficiaries with Advanced Cancer in response to the concerns[1] that emerged after stakeholders reviewed the NCD’s implementation instructions.

We are deeply concerned that the proposed policy is at odds with the current diagnostic landscape for germline NGS-based testing and the needs of Medicare beneficiaries with cancer. As written, this policy would reduce, rather than expand, Medicare beneficiary access to NGS-based testing for cancer.

We strongly urge the agency to make the following changes to the proposed coverage decision:

• Allow Medicare Administrative Contractors (MACs) discretion to cover all NGS-based germline tests for cancer patients, patients with suspected/diagnosed hematologic malignancy and serial minimal residual disease assessments; and
• Cover multiple NGS-based tests during a patient’s lifetime, when reasonable and necessary.

Germline testing in patients has demonstrated clinical utility by informing appropriate clinical decisions and positively impacting treatment choices, leading to improved cancer outcomes and survival rates. Information provided by NGS-based germline tests for cancer patients provides treating physicians with the ability to more accurately assess the best patient management approach such as surgical decisions, prognosis, and treatment options. As currently drafted the proposed manual language will deny access to patients with ovarian or breast cancer for two reasons. First, there are currently no FDA approved or cleared germline tests for breast and ovarian cancer, and thus no tests currently contain the criteria necessary to receive national coverage outlined in the proposed decision memo. Second, in the proposed memo, MACs are not allowed to cover germline tests for breast and ovarian cancer when the tests use NGS technology. While we are supportive of MAC coverage for these tests for patients at all stages, we urge CMS to allow MACs to determine coverage for all patients with a cancer diagnosis, including breast and ovarian cancer. Since there are no FDA-cleared or approved NGS-based germline tests currently available for breast and ovarian cancer, NGS-based germline testing for early-stage breast and ovarian cancer patients remains non-covered nationally and MACs would not have the ability to cover NGS-based germline tests for these cancers. Consequently, only tests utilizing older, less-advanced, and more expensive methods would be eligible for Medicare coverage for those with early-stage hereditary breast and ovarian cancer. In order to maintain Medicare patient access to critical testing to manage cancer treatment, CMS should revise its coverage policy to include MAC discretion to cover all other NGS-based tests to ensure patients with breast and ovarian cancer continue to have access to this testing.

As written, the NCD covers a test using NGS technology in a patient with “recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer.” Hematological malignancies are not staged according to this system, nor are all myeloid malignancies staged alike. We request that the text of the NCD be clear on this issue to ensure that Medicare beneficiaries with hematological diseases have access to tests using NGS technology as these tests in patients with myeloid malignancies reflect the current standard of care and should not be denied to Medicare beneficiaries. Using NGS technology to obtain genetic variation information underlies the classification of myeloid malignancies and has aided in the correct classification and prognostic tiering of these cancers. NGS-based testing has been recognized as an optimal and comprehensive laboratory testing methodology for routine clinical evaluation of hematologic and lymphoid diseases and has emerged as the current standard to guide clinical management decisions (including indications for target-specific therapy), improve prognostic risk stratification, and provide precise diagnostic sub-classification for patients with known or suspected myeloid and lymphoid diseases.

Additionally, we are concerned about the implications of the new proposed manual language that stipulates that a patient has “not been previously tested using NGS” and fear that this new language as well as the existing similar language for somatic testing limits coverage for a medically necessary test under a number of circumstances. It is not uncommon for many such germline-tested patients to have already undergone somatic NGS testing. For example, the Palmetto GBA MolDX local coverage determination (LCD) on Genetic Testing for Lynch Syndrome acknowledges that both a germline and somatic test may be medically reasonable and necessary under certain circumstances and adopts a testing approach to reflex to germline testing in certain patients that may have already received an NGS-based somatic test.[2] We support such an approach and recommend the NCD be adjusted to allow for certain cancer patients to receive both an NGS-based germline and somatic test when necessary.

New evidence-based guidelines establish the value of multiple NGS-based tests during the course of a patient’s treatment. An NGS panel at the time of diagnosis and subsequent NGS panels at progression on first and subsequent lines of therapy fulfill similar and unique purposes. We encourage the agency to expand the scope of the existing NCD to cover multiple tests during a patient’s lifetime, to ensure patient access to high quality NGS testing and to ensure accurate identification of targetable mutations at diagnosis and at recurrence or progression of cancer.

As patient advocates and providers, our goal is to ensure that high quality, clinically effective NGS-based testing continues to be available to all appropriate Medicare beneficiaries. We are encouraged by CMS’ willingness to reassess this policy. We look forward to CMS releasing the final NCD and welcome the opportunity to continue to work with CMS to ensure that the agency’s coverage policies do not negatively impact cancer patients.

Sincerely,

A Breath of Hope Lung Foundation
AliveAndKickn
ALS Crowd
AnCan' - Answer Cancer Foundation
Bladder Cancer Advocacy Network
Cancer ABCs, Inc.
Cholangiocarcinoma Foundation
Ciitizen
CLL Society Inc.
Colon Cancer Alliance for Research and Education for Lynch Syndrome
Colorectal Cancer Alliance
Fight Colorectal Cancer
Go2 Foundation for Lung Cancer
HIS Breast Cancer Awareness
ICAN, International Cancer Advocacy Network
International Society of Nurses in Genetics
Myeloma Crowd
National Alliance of State Prostate Cancer Coalitions
Prevent Cancer Foundation
Prostate Cancer International
Prostate Health Education Network, Inc.
Sharsheret
Supporting Our Sisters International Inc.
SURVIVEiT
Susan G. Komen
The American Society of Breast Surgeons
The Clearity Foundation
Triage Cancer
Us TOO International Prostate Cancer Education & Support
Young Survival Coalition

References:
[1] https://www.amp.org/AMP/assets/File/advocacy/Group_Stakeholder_Letter_NGSNCD-FINAL-1-31-2019.pdf
[2] Proposed Local Coverage Determination (LCD): MolDX: Genetic Testing for Lynch Syndrome (L35024), available at https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35024&ver=50&SearchType=Advanced&CoverageSelection=Local&ArticleType=BC%7cSAD%7cRTC%7cReg&PolicyType=Both&s=48&KeyWord=Lynch+syndrome&KeyWordLookUp=Title&KeyWordSearchType=Exact&kq=true&bc=IAAAACAAAAAA&.
cc: Tamara Syrek Jensen, JD, Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Joseph Chin, MD, MS, Deputy Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Lori Ashby, MA, Director
Division of Policy and Evidence Review, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Andrew Ward, PhD, Director
Evidence Development Division, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Rosemarie Hakim, PhD, Senior Science Advisor
Evidence Development Division, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
James Rollins, MD, PhD, Medical Officer
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Carl Li, MD, MPH, Medical Officer
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Kimberly Long, Lead Analyst
Coverage and Analysis Group
Centers for Medicare & Medicaid Services

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I have some comments on the National Coverage Decision [PHI Redacted] They are as follows:

• As is usually the case with cancer therapy, most thought goes immediately to women’s issues. In this instance the topic becomes breast cancer and ovarian cancer. Other cancers are lumped into the “other” category. Yet the incidence of prostate cancer in men is right on par with women and breast cancer both in terms of diagnosed cases and deaths. The same genetic proclivity markers such as BRACA2 and BRACA1 as well as other genetic markers effect men. When present these genetic markers often lead to death from very aggressive disease. So, men need to have a seat at the table in this “Decision” and be mentioned as players in this game.


• Both germline and somatic genetic testing are relatively new and emerging technologies and therefore there should be little or no restrictions placed on their availability from my perspective. The field is changing rapidly and new doors are opening up. One example is the need to test for “MSI” (Micro Satellite Instability) which opens the door for certain new and emerging therapies. [PHI Redacted] So, I am in favor of availability of repeat testing.


• The difference between Germline and Somatic testing needs to be spelled out pretty clearly and indicated when each is applicable and merited. Also, germline testing should be made available to adult children of any cancer patient who is diagnosed with a positive germline mutation.


• I think that people with significant family history of cancers should have access to germline genetic testing in their 30’s or 40’s before any diagnostic cancer is determined. This would open the door to the possibility of prophylactic procedures.

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Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore MD 21244

RE: National Coverage Analysis (NCA) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

The Advanced Medical Technology Association (AdvaMed) and AdvaMedDx commend the Centers for Medicare & Medicaid Services (CMS) for reopening the National Coverage Determination (NCD) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.¹ We are pleased to offer the following comments on the proposed Decision Memorandum.

AdvaMed member companies produce the medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatments. AdvaMedDx functions as an association within AdvaMed and its member companies produce advanced in vitro diagnostic tests that facilitate evidence-based medicine, improve quality of patient care, enable early detection of disease and often reduce overall health care costs. Our membership includes manufacturers engaged in the development of innovative diagnostics that support the advancement of public health, including next generation sequencing-based technologies. Throughout this letter, AdvaMed refers to both AdvaMed and AdvaMedDx.

We appreciate the opportunity to provide comments on the proposed expansion of coverage of NGS-based testing to germline (inherited) testing. These important tests and technologies play an integral role in personalized medicine and patient care management, and therefore access to these tests is critical for Medicare patients. We also appreciate and support the proposal to allow Medicare Administrative Contractors (MAC) the necessary discretion to consider and determine coverage of NGS-based germline testing for other cancers, where the status of the evidence is rapidly evolving.

As we have previously noted, NGS is a tool that can be used for many applications, from hematology/oncology to immunology and more. We continue to support creating a rational path to coverage for additional uses of NGS (such as initial diagnostic assessment, tracking diseases longitudinally, or where companion designation of a test is not plausible). Patient access to new NGS-based tests must be able to keep pace with the development of new clinical utility evidence.

Application to Testing for Germline Mutations and Hereditary Cancers

We appreciate CMS’s proposal to expand coverage under the draft NCD to germline mutation testing. We support CMS’s conclusions that the available evidence supports use of NGS as a diagnostic test for patients with risk factors for germline ovarian or breast cancers, where clinical indications for germline testing exist and the results of the test could impact the clinical management of those patients.

We note that the literature and existing guidelines do not distinguish between testing performed on an NGS platform and testing using other sequencing methods, such as Sanger sequencing, and we continue to voice our concerns that this will lead to disparate coverage policies for the same type of testing when performed on different platforms. Numerous existing tests performed on platforms other than NGS are migrating to NGS platforms. It would be non-sensical for Medicare coverage policy to cover a diagnostic test as reasonable and necessary when performed on one platform, but to non-cover an NGS-version of the same test.

Application to Testing for Treatment Monitoring and Repeat Testing

Many NGS-based diagnostic tests are indicated to aid in identifying patients who are eligible for targeted therapies regardless of the stage of cancer and/or recurrence. The proposed NCD, even with its proposed coverage expansion, still prohibits coverage of NGS-based testing for patients with earlier stage cancer and testing that requires repeated use of the test over time, such as identifying minimal residual disease or other monitoring uses. The NCD should not be a barrier to future developments in the field.

Local Coverage Determinations for NGS as a Diagnostic Test AdvaMed supports CMS’s proposal to allow discretion for MACs to determine coverage of NGS-based diagnostic tests for patients with cancer diagnoses other than breast or ovarian cancers (e.g., prostate cancer^{2, 3, 4, 5}). We agree that CMS coverage policy should not foreclose coverage in other cancers where the state of the evidence is continually evolving.

We urge CMS to remain flexible in its approach to coverage of future uses of NGS as a diagnostic test. Inevitably, new discoveries will continue to unfold, and important new therapies will be developed, outside of breast and ovarian cancer, including non-cancer uses. A flexible approach will safeguard existing coverage policies that predated the NCD, and enable coverage, either through national coverage or MAC discretion, that can provide clinicians and their patients access to this valuable tool as evidence is generated for new clinical uses.

Title Change and Other Technical Revisions

Finally, AdvaMed recommends that CMS revise the title of the NCD and make other technical revisions for conformity.

• We recommend revising the title of the NCD to reflect the expansion of coverage beyond patients with advanced cancer. AdvaMed supports other stakeholders’ recommendations to revise the title to “Next Generation Sequencing (NGS) for Treatment and Management of Cancer.” This title change would reflect CMS’s recognition of new, additional benefits of NGS as a diagnostic test, and would also keep open the potential for additional expansions of coverage in the future.


• We recommend specific changes in the new NCD language for germline testing. In two places, CMS uses the phrase “not been previously tested using NGS.” We believe this statement was not intended as drafted and should be revised to read “not been tested previously tested for the same germline gene or genes using NGS.”

  The language in the existing NCD (for patients with advanced cancer) reads “not been previously tested using the same NGS tests for the same primary diagnosis of cancer, or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician.” The language in the new section for germline testing should follow a similar rationale. A patient could, for example, have had prior NGS testing for another condition (e.g., a cardiac condition, sepsis, or other reason); however, this should not preclude the patient from receiving an NGS-based germline test.

• We recommend that CMS revise the language that follows section B.2. (under “Nationally Covered Indications”):
  Effective for services performed on or after [Month/XX][Day/XX], [20XX], the CMS proposes that NGS as a diagnostic laboratory test is reasonable and necessary, and covered nationally, when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

• We recommend that CMS revise the reference to Section B.1 in Section C (Nationally Non-Covered) to Section B as follows:

  Effective for services performed or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in Section B.1. above.

• We recommend that CMS add language at the end of Section D. (Other):
  Other uses of NGS testing in patients with cancer, not precluded by Section C, remain at the discretion of the Medicare Administrative Contractors (MACs).

Thank you for the opportunity to provide these comments. Please feel free to contact me at cbranham@advamed.org if you have any questions.

Sincerely,

Chandra N. Branham, JD
Vice President, Payment & Health Care Delivery Policy
AdvaMed

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1 See Proposed Decision Memo for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer (CAG-00450R), https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decisionmemo. aspx?NCAId=296 (Accessed October 29, 2019).
2 C.C. Pritchard, J. Mateo, M.F. Walsh, et. al., “Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer,” New England Journal of Medicine, published on July 6, 2016, at NEJM.org.
3 Robinson et al., 2015, Cell 161, 1215–1228, May 21, 2015, ©2015 Elsevier Inc., http://dx.doi.org/10.1016/j.cell.2015.05.001.
4 Modena, A, Iacovelli, R, Scarpa, A, et. al., “Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer,” Targeted Oncology, published online 11 July 2016.
5 Quigley et al., 2018, Cell 174, 758–769, July 26, 2018 © 2018 Elsevier Inc., https://doi.org/10.1016/j.cell.2018.06.039.

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November 29, 2019

Tamara Syrek Jensen, J.D.
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Sent electronically

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

On behalf of Johnson & Johnson, I am pleased to offer the following comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed National Coverage Analysis (NCA) Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R).

CMS SHOULD PROCEED WITH THE PROPOSAL TO INCLUDE GERMLINE TESTING AS PART OF NGS COVERAGE POLICY

We support the proposal to expand coverage under the proposed NCD to germline mutation testing using NGS as a diagnostic test for patients with risk factors for germline ovarian or breast cancers, where clinical indications for germline testing exist and the results of the test could impact the clinical management of those patients. Use of NGS technology for germline testing enables earlier detection and treatment, lowers overall costs and encourages individualized care for Medicare beneficiaries.

The information provided by an NGS assay is an important tool in helping clinicians and their patients make the best treatment decisions and holds great promise to advance personalized medicine. Because a comprehensive understanding of a cancer’s genetic makeup is critical for planning a patient’s treatment pathway and therapy selection, hereditary germline testing, like somatic testing, must be available to clinicians. Germline testing compliments somatic testing. To this end, we support extending coverage to germline hereditary testing for breast and ovarian cancers under the proposed for NGS.

To that end, there was some initial confusion whether the proposed NCD would continue to cover somatic testing using NGS for patients with recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer after the effective date of this proposed NCD.  Our understanding at this time, however, is that the proposed NCD would add coverage of NGS germline tests to the existing coverage described by the existing NCD without restricting the current NCD in any way.  If that is not the case, then we would oppose any such coverage restriction, particularly without more clearly announcing such a policy and accepting further public comment.

CMS SHOULD CONSIDER INCLUDING NGS GERMLINE TESTING FOR METASTATIC CASTRATION RESISTANT PROSTATE CANCER TO THE FINAL NCD

We believe the policy specifying only germline testing for breast and ovarian cancers is too narrowly defined.   There is ample evidence that men with the Metastatic Castration Resistant Prostate Cancer have a significantly higher incidence of germline mutations in genes mediating DNA repair processes and recent data for drugs in the PARP inhibitor class strongly suggest a relationship between a positive BRCA test and response to these novel drugs.[1],[2],[3],[4] Therefore we ask that CMS consider the addition of prostate cancers to the list of germline mutations included in the NCD.

RECOMMEND ALLOWING COVERAGE FOR CLINICALLY INDICATED TREATMENT MONITORING AND REPEAT TESTING

Many NGS-based diagnostic tests are indicated to aid in identifying patients who are eligible for targeted therapies regardless of the stage of cancer and/or recurrence. The proposed NCD, even with its proposed coverage expansion, still prohibits testing that requires repeated use of the test over time, such as identifying minimal residual disease or other monitoring uses.

While the overall policy affords a number of Medicare beneficiaries access to testing- with this limitation many of those same beneficiaries’ cancer will progress in time.   This progression affords new targets for new therapies and NGS testing may be a more relevant and efficient platform by which to characterize the causes of a patient’s progression and further direct therapeutic intervention.   We therefore recommend coverage of repeat testing based on the medical necessity of the patient to evaluate treatment options.

Johnson & Johnson appreciates the opportunity to comment on this NCA. Please feel free to contact us if there is any further information we can provide or if you have any questions about the topics discussed in our comments.

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[1] C.C. Pritchard, J. Mateo, M.F. Walsh, et. al., “Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer,” New England Journal of Medicine, published on July 6, 2016, at NEJM.org.

[2] Robinson et al., 2015, Cell 161, 1215–1228, May 21, 2015, ©2015 Elsevier Inc., http://dx.doi.org/10.1016/j.cell.2015.05.001.

[3] Modena, A, Iacovelli, R, Scarpa, A, et. al., “Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer,” Targeted Oncology, published online 11 July 2016.

[4] Quigley et al., 2018, Cell 174, 758–769, July 26, 2018 © 2018 Elsevier Inc., https://doi.org/10.1016/j.cell.2018.06.039.

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November 29, 2019

Administrative File: CAG-00450R
Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244-1850

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

The Connected Health Initiative (CHI) appreciates the opportunity to provide input to the Centers for Medicare & Medicaid Services (CMS) on its proposal to recognize that there is a sufficient evidence base to expand coverage of Next Generation Sequencing (NGS) as a diagnostic laboratory test with respect to ovarian or breast cancer under certain conditions.¹ We support CMS’ proposal and endorse CMS’ collaboration with industry stakeholders as this coverage expansion will be implemented throughout the country.

CHI represents a broad consensus of stakeholders across the healthcare and technology sectors. Our mission supports the responsible and secure use of digital health innovations throughout the continuum of care to improve patients’ and consumers’ experience and health outcomes. We seek to partner with the Department of Health and Human Services (HHS) in realizing the benefits of an information and communications technology-enabled American healthcare system. CHI and its members commit to responsibly advancing the role of technology such as NGS in preventing and treating disease.

CHI appreciates the opportunity to provide comments as CMS considers expanding coverage of NGS to address ovarian and breast cancer based on its evidence. Diagnostic tools—using artificial/augmented intelligence (AI), powered by streams of data and algorithms—can and should serve as a vital means of realizing the benefits of therapeutics. Access to these tools will advance the personalization of healthcare, improve outcomes, and encourage greater proactive engagement by patients.

The widest range of use cases possible should utilize NGS. CHI supports its use for NGS tests of inherited mutations to identify those with inherited cancer (at any stage) who may benefit from targeted treatments based on results of the test. Such testing aids in finding the most appropriate treatments for those suffering from advanced cancers.

CHI believes that a strong evidence base justifies expanded coverage for NGS,² and that the evidence demonstrates that NGS technology’s use in germline testing is vital, empowering much earlier detection and treatment of disease at more efficient costs. Further, the use of NGS helps to personalize medicine, making Medicare beneficiaries more proactively engaged in their own care. CMS should, in as flexible an approach as possible, expand coverage to patients with earlier stage cancers and applications for repeat NGS testing in order to permit identification of cancer at the earliest point possible to improve outcomes and to encourage proactive health changes.

CHI appreciates the opportunity to submit its comments to CMS on this important matter. We look forward to assisting CMS in realizing an advanced technology-enabled care continuum that provides maximum value to patients at the lowest costs.

Sincerely,

Brian Scarpelli
Senior Global Policy Counsel

Alexandra McLeod
Policy Counsel

Connected Health Initiative
1401 K St NW (Ste 501)
Washington, DC 20005

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1 See Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R), https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=296 (Accessed November 27, 2019) (Proposed Coverage Determination).
2 Proposed Coverage Determination at Sec. VII.

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November 27, 2019

Ms. Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen:

On behalf of the American Society of Clinical Pathology (ASCP), I am writing to provide comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAD-00450R). ASCP supports coverage of advanced diagnostics, such as those utilizing next generation sequencing (NGS) methodologies, that can improve the ability of physicians to diagnose and treat patient diseases like cancer.

We believe that proposing coverage for germline NGS for all stages of cancer is a significant improvement over last year’s NGS NCD for Medicare Beneficiaries with Advanced Cancers (CAG-00450N), which does not allow Medicare to cover NGS for patients at increased risk of cancer or with early stage cancers. That said, we are concerned that this proposed coverage policy would not extend coverage to women at increased risk for breast or ovarian cancers or for germline NGS laboratory developed tests (LDTs) for ovarian and breast cancer. We are also concerned about the proposal to limit Medicare beneficiaries to one NGS service during their lifetime, as tumors are known to change at the molecular level as they progress to a higher stage resulting in potentially new targets for therapeutic intervention. Otherwise stated, once-in-a-lifetime NGS may be acceptable for germline analysis, but greater than one NGS somatic or tumor NGS assay may be appropriate due to tumor evolution. ASCP believes that these shortcomings undermine quality patient care and limit the ability of clinical laboratories to provide patients and their providers with the diagnostic services best-suited to their medical needs.

The ASCP is a 501(c)(3) nonprofit medical specialty society representing over 100,000 members. Our members are board certified pathologists, other physicians, clinical scientists (PhDs), certified medical laboratory scientists/technologists and technicians, and educators. ASCP is one of the nation’s largest medical specialty societies and is the world’s largest organization representing the field of laboratory medicine and pathology. As the leading provider of continuing education for pathologists and medical laboratory personnel, ASCP enhances the quality of the profession through comprehensive educational programs, publications, and self-assessment materials.

I. Coverage Should be Extended to Woman at Increased Risk of Cancer

ASCP notes that the American College of Obstetricians and Gynecologists’ clinical guidelines support genetic testing for women with cancer as well as women unaffected with cancer that may be at increased risk of cancer due to an inherited predisposition to breast, ovarian, tubal or peritoneal cancer. CMS’s proposed coverage memo would cover NGS testing of women with ovarian and breast cancer, but it would not cover woman at risk of developing such cancers. As CMS notes in its coverage memo, knowing the origins of cancer helps guide the course of patient treatment. That said, it can be can be equally, if not more, important to identify certain genetic markers that aid with the early detection of cancer. ASCP believes that because ovarian cancer lacks an effective screening test, and usually is not detected until it has progressed to an advanced stage, CMS should cover NGS testing of women at increased risk of cancer but who have not yet been diagnosed, provided they meet consensus criteria for screening. In line with this request and because this memo covers early stage cancers, ASCP also believe that this coverage policy should be retitled. Identifying it as specific to “advanced cancers” could result in patients and providers not being aware that NGS testing for non-advanced stage cancers are covered.

II. CMS Should Extend Coverage to NGS LDTs for Ovarian and Breast Cancer

Under the proposed coverage memo, germline NGS for breast and ovarian cancers would have to obtain FDA-approval to receive Medicare reimbursement via a National Coverage Decision (NCD). While the proposal would allow NGS LDTs to obtain coverage via a local Medicare Administrative Contractor (MACs), it would eliminate the possibility of Medicare coverage for NGS LDTs for breast and ovarian cancers. Such a policy approach would be harmful to patient care. ASCP is concerned that the proposed policy relegates LDTs to a second-tier status compared to FDA approved- or cleared-diagnostics. LDTs are increasingly being integrated into standard practice for diagnosing and managing disease, predicting the risk of developing disease, and informing decisions about lifestyle and behavior—particularly molecular genetic tests for which there are few commercial tests available. They have become indispensable tools in today’s practice of medicine and their potential impact on patient care is poised to increase dramatically in the coming years.

Many of the key innovations in the pursuit for better diagnostics are the result of research by academic medical centers, reference laboratories, and discovery centers--in the form of LDTs. The current peer-review and local assay validation processes mandated by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) has well-served patients and the clinical laboratory testing community for decades. Based on our experience, CLIA has done a satisfactory job of ensuring quality laboratory testing and patient care. As a result, we object to coverage policies that disincentivize, if not discourage, the development of new diagnostic technologies by academic medical centers, reference laboratories and discovery centers.

Importantly, LDTs are able to bring the latest advancements in diagnostic research to market faster than FDA’s oversight framework. In addition, we note that these innovation centers often lack the financial resources to navigate the FDA regulatory requirements as well as diagnostic manufacturers. As a result, we are concerned that potential for non-coverage of LDTs, such as NGS for ovarian and breast cancers, erodes the financial incentive for academic medical centers, reference laboratories and discovery centers to conduct the research necessary to improve patient diagnostics. From our perspective, this proposed policy creates a very real and formidable disincentive for clinical laboratories to invest in the development of LDTs and this will have negative repercussions for patient care.

CMS should be aware that there are currently no FDA-approved or -cleared NGS diagnostics for germline testing for breast or ovarian cancer. Not allowing for coverage of LDTs means that this policy does not provide coverage for ovarian or breast cancers using certain NGS methodologies. To rectify this flaw, ASCP urges that CMS allow coverage of all LDTs utilizing NGS technology provided it is developed within the applicable CLIA requirements.

III. CMS coverage should allow for multiple testing events utilizing NGS technologies

ASCP is also concerned about the proposed limitation of one NGS per lifetime. This language is present in both the germline and somatic sections of the national coverage decision. This could result in an interpretation that a patient who has had somatic testing may be denied germline testing, which could fail to detect therapeutically targetable genetic driver mutations in the malignancy. Additionally, a patient with a second cancer diagnosis may not have coverage, if a germline or somatic NGS test was performed. Finally, a patient may be denied another somatic test if their cancer progresses over time or recurs. As a result, ASCP requests that CMS change its coverage policy to allow for multiple NGS-based tests during a patient’s lifetime, when reasonable and necessary.

ASCP appreciates the opportunity to comment on this proposed NCD. If we can be of any assistance, please contact me or Matthew Schulze, Director of the ASCP Center for Public Policy at (202) 735-2285 or Matthew.Schulze@ASCP.org.

Sincerely,

Gene Siegal, MD, PhD, FASCP
President, ASCP

cc: Joseph Chin, MD, MS, CMS/OA/CCSQ/CAG
Kimberly Long, CMS/OA/CCSQ/EAG/DPER
Lori Ashby, MA, CMS/OA/CCSQ/CAG/DMSS
Andrew Ward, PhD, CMS/OA/CCSQ/CAG/EDD
Rosemarie Hakim, PhD, CMS/OA/CCSQ/EAG/EDD
James Rollins, MD, PhD, CMS/OA/CCSQ/CAG/DPER
Carl Li, MD, MPH, CMS/OA/CCSQ/EAG/EDD

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, MD 21244

Re: Reconsideration of the National Coverage Determination on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

The Cancer Support Community (CSC) appreciates the opportunity to comment on CMS’ reconsideration of the National Coverage Determination on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (NCD). As the largest professionally led nonprofit network of cancer support worldwide, CSC including its Gilda’s Club affiliates, is dedicated to ensuring that all people impacted by cancer are empowered by knowledge, strengthened by action, and sustained by community. CSC achieves its mission through three areas: direct service delivery, research, and advocacy. The organization includes an international network of Affiliates that offer the highest quality social and emotional support for people impacted by cancer, as well as a community of support available online and over the phone. The Research and Training Institute conducts cutting-edge psychosocial, behavioral, and survivorship research. CSC furthers its focus on patient advocacy through its Cancer Policy Institute, informing public policy in Washington, D.C. and across the nation. Overall, we deliver more than $50 million in free, personalized services each year to individuals and families affected by cancer nationwide and internationally.

As noted in previous letters to CMS, CSC acknowledges the importance of NGS in delivering personalized medicine for cancer patients. We appreciate CMS’ attempt to initiate a regulatory pathway for technologies that are used to identify targeted, personalized treatments for patients with advanced cancer. We also recognize the complexities of this process and support coverage and access to the most innovative technologies that will make personalized medicine the standard of care for all individuals diagnosed with cancer. Ultimately, we believe that CMS should make coverage decisions that contribute to the right patient having access to the right care at the right time based on individual needs, values, and preferences.

We are concerned that the revised NCD will limit access to germline testing for breast and ovarian cancer patients who do not currently have the option of an FDA-approved test. Further, MACS are restricted from covering germline tests for these cancers when those tests use NGS technology. As such, MACs should have discretion to cover this testing in Medicare beneficiaries with cancer when it is supported by National Comprehensive Cancer Network (NCCN) guidelines, medical society guidelines, ordered by a treating physician, or medically necessary to guide decision-making.

We continue to have concerns regarding coverage for NGS tests for graded cancers such as hematologic and myeloid malignancies. The uncertainty created by the NCD, which states that that it would cover a test using NGS technology in a patient with “recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer,” is concerning for patients. We urge clarification to ensure that Medicare beneficiaries with these types of cancers do not lose access to NGS-based testing that is critical to their decision making, treatment options, and health outcomes.

We also have concerns regarding the impact if CMS limits coverage to a patient that has “not been previously tested using NGS.” We encourage the agency to consider the impact of this decision and support patient access to NGS testing at appropriate time points both at diagnosis and recurrence.

Thank you for the opportunity to provide this feedback. Our comments reflect our belief that these changes would allow Medicare beneficiaries to benefit from appropriate testing at the right time, as technology advances, and evidence-based guidelines develop. We urge you to consider these implications in your reconsideration of the NCD. If we can serve as a resource, please don’t hesitate to contact me at efranklin@cancersupportcommunity.org.

Sincerely,

Elizabeth Franklin, MSW
Executive Director, Cancer Policy Institute
Cancer Support Community Headquarters

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November 26, 2019

Tamara Syrek Jensen, J.D.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

BY ELECTRONIC DELIVERY

Re: Proposed Decision Memo for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

Novartis appreciates the opportunity to provide comments in response to the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.

Novartis provides healthcare solutions that address the evolving needs of patients and societies worldwide. Our broad portfolio includes innovative pharmaceuticals, oncology medicines, high-quality generic and biosimilar medicines. At Novartis, we are united by a single purpose: reimagining medicine to improve and extend people’s lives. Through science-based innovation, we address some of society’s most challenging healthcare issues. Every day we work to discover and develop breakthrough treatments and find new ways to deliver them to as many people as possible.

We applaud CMS’ efforts to support better biomarker testing through coverage of NGS for Medicare beneficiaries. Allowing Medicare beneficiaries access to NGS testing could lead to more appropriate treatment through precision medicine. NGS tests allow for rapid characterization of large sections of an individual genome, enabling physicians to more accurately diagnose and treat illnesses; patients and physicians to make smarter decisions about treatment options; and researchers to continue to advance science and precision medicine.

The National Coverage Decision (NCD) for NGS highlights the complex nature of the use of this powerful tool. As the translational science around NGS continues to evolve, we believe CMS’ policies should allow for clinically appropriate use of NGS whenever medically necessary.

Novartis recommends changes to the proposed coverage decision whereby a patient has “not been previously tested using NGS” as this potentially equates to a once-per-lifetime restriction on NGS testing for Medicare beneficiaries. Such a limitation on NGS testing may result in patients not receiving medically appropriate testing over the course of their treatment that could identify recurrence and/or progression of their cancer. Furthermore, the creation of artificial limits on NGS testing may stifle innovation and negatively impact the development and approval of new technologies and therapies that enable precision medicine.

CMS should consider the possibility of clinically appropriate NGS testing when a physician suspects that a novel mutation has arisen. For example, patients being treated for non-small cell lung cancer often acquire a resistance to tyrosine kinase inhibitors (TKI) drugs after a period of treatment response, which is primarily attributable to the rise of new mutations. After receiving epidermal growth factor receptor (EGFR) TKI therapy, EGFR T790M mutation occurs in around 50-60% of resistant cases. Future testing options, such as longitudinal testing, could detect these resistant mutations and allow physicians to update their treatment protocol, possibly even before the detection of disease progression. This would not be possible under the current NGS NCD testing restrictions.

Similarly, as the translational evidence around NGS testing matures, it can reasonably be expected that newly actionable, clinically validated biomarkers may be promoted to Companion Diagnostics on existing multi-gene NGS panels. Patients who have already been tested using NGS should not be denied access to a repeat test that includes an expanded panel of biomarkers with clinical claims, which may be able to detect specific mutations associated with a newly approved life-saving or life-extending therapy. An example is the post marketing requirement for an In Vitro Diagnostic test to support the labeling for the safety and effective use of larotrectinib for patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusions in solid tumor specimens.

Restricting patient access to a single test per lifetime for the same primary cancer neither accounts for current clinical practice (e.g., re-testing at progression) nor for the rapid and ongoing clinical development of this testing modality (e.g., the ongoing addition of biomarkers to existing panels,). Novartis supports CMS’ focus on coverage of testing that can lead to life-saving therapy for its beneficiaries. However, in order to ensure that patients have access to potentially life-saving NGS testing, we urge CMS to expand the scope of the proposed NCD to cover multiple tests during a patient’s lifetime when clinically appropriate.

We appreciate the opportunity to comment and would be happy to provide further information regarding our comments above. Please feel free to contact me at 862-778-3284 if we can provide further assistance.

Sincerely,

Leigh Anne Leas /s/

Leigh Anne Leas
Vice President and North America Head, Public Policy
Novartis Services Inc.

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November 27, 2019
Tamara Syrek Jensen Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen,

We appreciate the opportunity to provide feedback on behalf of The US Oncology Network’s Genetic Risk Evaluation and Testing (GREAT) Program, as program medical directors and practicing medical oncologists. This proposed NCD directly affects our practices and patients. We have a comprehensive cancer genetics program across our network, which includes oncologists, genetic counselors and trained APP providers. In addition, our network of over 1,000 oncologists are navigating treatment decisions based on NGS tumor and germline genetic testing in community cancer centers across the country.

We agree with many of the proposed coverage policy changes. We agree with the CMS summary statement that the “accurate diagnosis of inherited cancer by NGS through identification of germline mutations directly guide physician treatment and improve some patient health outcomes”. We appreciate the proposed changes made to include cancers of all stages, and for coverage of patients with breast or ovarian cancer. We appreciate the option to consider other cancers, and would recommend coverage extended to many other cancers, including pancreatic, metastatic prostate, and colon cancers.

Our main concerns regarding this NCD are as follows:

• We disagree with the limitation in this NCD that NGS testing will not be covered if prior NGS testing has taken place. This means that cancer patients who have tumor NGS testing that identifies a significant gene mutation that is suspicious for being inherited, such as a BRCA1 mutation, would not have coverage for needed germline NGS testing to determine if the mutation is inherited. It is important that somatic testing does not restrict germline testing options. If these patients cannot get coverage for germline NGS testing, they and their physicians will not know if they have a germline mutation - knowledge that could guide chemotherapy decisions, provide knowledge regarding high future separate cancer risks, and provide relatives with important cancer risk information. This limitation is a real barrier for clinicians providing care to these patients, and ignores the value of effective cancer prevention and targeted surveillance strategies.


• In addition, the requirement that the NGS tests must have FDA approval or clearance is too restrictive, and imposes an additional barrier for clinicians. The time and costs to labs of this requirement does not seem to work for this extremely dynamic area of medicine. NGS technology changes too fast for tests to be static through regulation. Currently very few germline cancer panel tests are FDA approved, including the most frequently ordered cancer panels in our network.

In addition, although not in the stated scope of this NCD, we urge CMS to extend NGS testing coverage to unaffected individuals with personal and family histories that meet medical criteria for testing. This includes individuals with a known gene mutation in their family who qualify for cascade testing for the mutation in their family. We also support the proposed change to designate certified genetic counselors as CMS health providers who can bill under Medicare, so that patients can get accurate information from trained professionals in this complex specialty. Our organization supports the current house bill, the Access to Genetic Counselor Services Act of 2019. HR 3235, as part of this effort.

Thank you for working to improve access to needed NGS testing for our patients.

Sincerely,

Patricia Rodriguez, MD and Lucy Langer, MD
Medical Directors of the GREAT Program, The US Oncology Network
Virginia Cancer Specialists, and Compass Oncology

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Memorial Sloan Kettering Cancer Center (MSK) appreciates the opportunity to offer feedback on the proposed decision memo on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer, which has been revised to address germline testing. MSK is a National Cancer Institute-designated comprehensive cancer center devoted solely to the research and treatment of cancer. We are committed to advancing clinical care through scientific innovations, including by advancing personalized medicine.

MSK developed and administers the MSK-IMPACT™ test, which uses NGS for rapid identification of mutations in 468 cancer-related genes. This test identifies genetic alterations implicated in cancer predisposition, as well as genetic mutations that can be targeted by U.S. Food and Drug Administration (FDA)-approved cancer therapies, making it a valuable tool in determining the appropriate and most effective plan of care for many cancer patients. MSK-IMPACT was cleared as a tumor profiling test by the FDA in 2017. MSK-IMPACT is unique in requiring a normal control to differentiate somatic mutations from germline alterations and mutations associated with clonal hematopoiesis, which enhances the quality of the assay as compared to tumor-only assays by unambiguously revealing the origin of all alterations to inform the proper administration of therapy.

Because somatic and germline testing both play an important role in cancer treatment, MSK has also developed a germline MSK-IMPACT assay, which has been approved by the New York State Department of Health but has yet to be reviewed by the FDA. The germline MSK-IMPACT assay allows the efficient and cost-effective identification of mutations in highly penetrant cancer predisposition genes (defined as genes in which germline mutations confer increased risks of cancer) that cause hereditary cancer syndromes. The incorporation of cancer genetic testing into oncology marked one of the first applications of personalized genomics in medicine, because it allowed tailored cancer screening, prevention, and, in some cases, therapeutic measures. In turn, this has potential to provide substantial cost-effective health benefits with respect to cancer treatment of patients and cancer prevention in healthy individuals.

As has now been recognized in the proposed decision memo, somatic and germline testing are critical tools in making informed treatment decisions for patients with a cancer diagnosis. MSK supports revisions to the national coverage policy to ensure that Medicare beneficiaries with both early and late stage ovarian or breast cancer have access to germline testing. We also strongly support the revised proposal to permit Medicare Administrative Contractors to determine local coverage for germline testing for patients with other types of cancer.

While the current decision memo represents an improvement over the previously issued coverage policy, MSK has several outstanding concerns not addressed by the revisions. First, while we commend the elimination of the “companion in vitro diagnostic” requirement in the context of coverage for germline testing, we continue to believe that U.S. Food and Drug Administration (FDA) approval or clearance and an FDA approved or cleared indication for use in that patient’s cancer should be adequate for coverage in both the germline and somatic settings. Requiring companion in vitro diagnostic designation for somatic testing is unnecessarily limiting and has disincentivized the use of the FDA’s third-party review pathway. In addition, we are concerned that the requirement that the patient have “not been previously tested using NGS” fails to appreciate the necessary differences between somatic and germline testing using NGS. Currently, MSK is unaware of any FDA approved or cleared germline tests using NGS methodologies, meaning that national coverage policies for NGS testing in patients with cancer remain relatively restricted.

As an academic based laboratory, we want to ensure Medicare beneficiaries continue to have access to all appropriate evidence-based testing, both germline and somatic. Advancing cancer care is our mission, and we believe that CMS should modify the current policy to allow coverage for both germline and somatic settings, if an assay has an FDA-cleared indication.

Coverage of Germline Testing

MSK strongly supports revisions to the NCD to clarify that NGS testing for germline mutations may be covered for beneficiaries with early and late stage breast or ovarian cancer, as well as to permit MACs to determine coverage for germline testing in other types of cancer locally. Detection of germline mutations in patients with cancer of any stage is critical to allowing physicians and patients to select a treatment plan based on a fully informed picture of that individual’s cancer risk. Our understanding of the genetic basis of cancer susceptibility has improved significantly in the last 30 years. Highly penetrant cancer predisposition genes have been identified and shown to cause hereditary cancer syndromes with Mendelian modes of inheritance. These genes include BRCA1 and BRCA2 in hereditary breast-ovarian cancer syndrome, DNA mismatch repair genes in Lynch syndrome, and APC in familial adenomatous polyposis. The identification of the genetic basis of such syndromes has had a powerful impact on the practice of preventive oncology. The incorporation of cancer genetic testing into oncology marked one of the first applications of personalized genomics in medicine, because it allowed tailored cancer screening, prevention, surgical risk-reduction, and, in some cases, therapeutic measures.

The MSK-IMPACT panel includes all the cancer predisposition genes of clinical interest and a subset of 88 tumor suppressor genes and oncogenes for germline clinical testing purposes are analyzed with patient consent after matched tumor-normal sequencing (i.e., ‘agnostic’ germline genetic testing). Of these 88 genes, an additional subset of genes is also utilized for small panel ‘primary’ germline-only testing as indicated by various factors including family history, patient disease presentation, and inherited cancer risk assessed by MSK genetic counselors.

Among our cohort of >11,000 cancer patients who have undergone agnostic germline genetic testing via MSK-IMPACT, we find that 17% harbor a pathogenic or likely pathogenic germline mutation in one of the 88-gene cancer susceptibility genes, with 11% of the overall cohort having a pathogenic or likely pathogenic mutation in a high-penetrance (BRCA1/2, MLH1, MSH2, TP53, CDH1, etc.) or moderate-penetrance (ATM, CHEK2, BRIP1, etc.) cancer predisposition gene. We have published in the peer-reviewed literature these same findings in an initial set of patients studied [Mandelker et al, JAMA, 2017]. For these cancer patients, initial surgical treatment for their disease may be altered from standard recommendations based upon the presence of the germline mutation to include bilateral mastectomy (BRCA1/2, TP53), total colectomy (APC, Lynch syndrome, etc.), or total gastrectomy (CDH1). In some cases, such as VHL germline carriers with renal masses, observation as opposed to surgery is recommended (NCCN guidelines) for smaller tumors. Notably, changes to standard surgical approaches based on germline findings are especially relevant for early-stage cancer patients where surgical treatment remains the cornerstone of oncological management.

Germline testing has been emphasized in recent 2018 and 2019 updates to NCCN guidelines for breast, ovarian, prostate and pancreatic cancer. Based on these updates, the use of germline and somatic testing has become increasingly important in making treatment decisions for these patients for early use of platinum chemotherapy, PARP inhibitor eligibility and pembrolizumab in later lines of treatment (following tumor testing for microsatellite instability or mismatch repair deficiency). For example, at our institution, of 419 patients with diverse cancer diagnoses, who harbored germline BRCA1/2 mutations that we identified via MSK-IMPACT, 28.6% (120 patients) received a PARP-inhibitor, a targeted treatment for BRCA1/2 associated cancers, during their treatment course. This includes 41 patients with ovarian cancer, 32 patients with pancreatic cancer, 21 patients with breast cancer, 13 patients with prostate cancer, and 13 patients with other cancer types. While mutations in PALB2, a gene also associated with homologous recombination repair, were less common, 20% of the 45 PALB2 mutation carriers received a PARP inhibitor. Additional alterations in medical management resulting from germline genetic testing are harder to track and include, among many other examples, the NCCN supported recommendation not to administer adjuvant chemotherapy in stage II colorectal cancer patients with Lynch syndrome or microsatellite instable tumors, as well as the decision to use carboplatin over taxanes as first-line treatment for BRCA1/2-associated metastatic triple negative breast cancer (Tutt et al., Nat Med 2018).

PARP inhibitors exploit a synthetic lethal strategy to target DNA repair pathway in the tumor and have received FDA approvals for adult patients with germline or somatic BRCA1/2 mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer as well as patients with germline BRCA-mutated, Her-2 negative metastatic breast cancer who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. On-going trials are looking at PARP inhibitors for treating prostate cancer in men with germline or somatic BRCA or other mutations, as well as treating pancreatic cancer in people with BRCA1/2 and other inherited mutations.

Revisions to the Test Specifications for Coverage

The companion diagnostic designation required for coverage of FDA approved and cleared tests under the NCD, which remains a requirement for somatic testing, is unnecessarily limiting and should be eliminated. As noted earlier, MSK-IMPACT was granted clearance by the FDA as an in vitro diagnostic tumor profiling test in 2017. Unlike tests designed to detect just one cancer biomarker that may indicate the use of a single drug, MSK-IMPACT compares tumor tissue to a “normal” sample of tissue or cells from the same patient to detect genetic alterations that might help guide treatment options. The FDA noted that the biomarker information made available by MSK-IMPACT can have a significant effect on care planning and outcomes.

As is the case with FDA-approved companion diagnostics, MSK-IMPACT reliably identifies the presence of somatic mutations in beneficiaries with advanced cancers for which mutation-targeting therapies are approved, i.e., non-small cell lung cancer, melanoma, colorectal cancer, and ovarian cancer. Based on submission of extensive evidence, the FDA specifically cleared MSK-IMPACT to facilitate the clinical interpretation of detected mutations, including of cancer mutations with evidence of clinical significance, such as EGFR, KRAS, BRAF, BRCA1/2 (somatic), as well as microsatellite instability, each of which is targeted by specific FDA-approved therapies. In issuing de novo authorization for MSK-IMPACT, FDA explained that, “Its ability to detect genetic mutations (analytical performance) was evaluated for precision, accuracy and limit of detection. Results indicated that the assay is highly accurate (greater than 99%) and capable of detecting a mutation at a frequency of approximately 5% (range of 2-5%).”

Nevertheless, MSK-IMPACT is still not covered under the recent proposed NCD revisions [except where authorized under a local coverage determination (LCD)], because FDA approval or clearance as a companion diagnostic is also necessary for coverage. However, it remains difficult to discern what, if any, advantage is gained by the NCD’s requirement for companion diagnostic designation. This is particularly true given that a single companion diagnostic designation for a test is adequate to ensure coverage for any cancer for which the test has an FDA-approved or cleared indication. For example, an NGS test with an FDA companion diagnostic designation applicable to a lung cancer therapy would be covered for a patient with lung cancer, but also for a patient with breast, prostate, or some other type of cancer, so long as the test is also indicated for use in those cancers. In this scenario, there is no practical difference, particularly in terms of evidence supporting clinical benefit, between FDA authorized tests with and without companion diagnostic designation.

Since the release of the final NCD on NGS testing early last year, MSK has been working with the FDA to secure companion diagnostic designation for MSK-IMPACT. In our ongoing discussions with the FDA, we have come to understand that companion diagnostic designation for NGS tests is not currently available through the 510K clearance pathway, meaning that the more costly and administratively onerous premarket approval process is the only viable pathway to coverage under the final NCD. Given the significant investment of time and resources required to secure a companion diagnostic designation and premarket approval, Medicare beneficiaries’ access to innovative tests like MSK-IMPACT continues to be unnecessarily restricted by the NCD and testing is ultimately rendered more expensive. Further, the companion diagnostic requirement has substantially undermined the incentive for other academic medical centers or test developers to pursue the FDA’s third-party review pathway, which was charted by MSK and announced as part of FDA’s efforts to enhance oversight of laboratory developed tests. We urge you to revise the NCD to remove this criterion and cover NGS assays that are FDA cleared for germline and/or somatic testing.

We appreciate your ongoing commitment to ensure that Medicare beneficiaries with cancer have access to clinically indicated testing for both tumor and germline mutations. If we can be a resource to you by providing technical expertise moving forward, please feel free to call on us. We would be happy to answer any questions you may have or provide further background.

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November 27, 2019

Tamara Syrek Jensen, J.D.
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Sent electronically

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

The Personalized Medicine Coalition (PMC), a multi-stakeholder group comprising more than 200 institutions across the health care spectrum, thanks the Centers for Medicare and Medicaid Services (CMS) for reconsidering the National Coverage Determination (NCD) for Next Generation Sequencing (NGS) in Advanced Cancer after hearing concerns that the NCD, as previously written, would have limited beneficiary access to germline testing for certain inherited cancers. PMC appreciates that the newly proposed decision memo expands coverage of tests utilizing NGS technology to Medicare beneficiaries with, or at risk for, inherited breast or ovarian cancer at any stage. This memo is an improvement from CMS’ original NCD for NGS-based tests, though we believe it still leaves significant gaps in coverage that we urge you to address in the final policy.

Personalized medicine is an evolving field that uses diagnostic tools to identify specific biological markers, often genetic, to help determine which medical treatments and procedures will be best for each patient. By combining this information with an individual’s medical history, circumstances, and values, personalized medicine allows doctors and patients to develop targeted prevention and treatment plans.

Personalized medicine is helping to shift the patient and provider experience away from trial-and-error treatments of late-stage diseases in favor of more streamlined approaches to disease prevention and treatment, which will lead to improved patient outcomes, a reduction in unnecessary treatment costs, and better patient and provider satisfaction. PMC’s members are leading the way in personalized medicine and recommend that patients who may benefit from this approach undergo appropriate testing and tailored treatment as soon as possible during their clinical experiences.

NGS technologies have played an essential role in advancing our understanding of the altered genetic pathways involved in human cancer. PMC appreciates CMS’ recognition that NGS is an important technology for identifying cancer patients who may benefit from a specific treatment path. We share CMS’ growing enthusiasm for the diagnostic innovation upon which personalized medicine depends, and we appreciate your interest in putting in place policies that will shape an industry with great potential to make the health system more efficient.

PMC applauded CMS in 2018 when the agency issued its first NCD for somatic-based tests utilizing NGS technology that have been approved or cleared by the Food and Drug Administration (FDA) for use on Medicare beneficiaries with late-stage cancers. In our 2018 comments on the proposed decision memo, PMC indicated that it shared concerns raised by the medical community that the proposed national coverage criteria were too restrictive and ran counter to processes firmly established in medical practice. It came to our attention in early 2019 that the terms of the NCD would apply to both somatic and germline NGS-based testing for patients with cancer, thereby extending the non-coverage provisions in the NCD to NGS-based testing for Medicare beneficiaries with early-stage cancer and those at risk for developing certain hereditary cancers.

The comments that follow build on issues raised by PMC in January of 2018 and May of 2019 regarding the scope of the proposed NCD and how the NCD could impact coverage for clinical testing services already employed in patient care as well as those that will be developed in the future.

Statement of Neutrality

Many of PMC’s members will present their own responses to CMS and will actively advocate for those positions. PMC’s comments are designed to provide feedback so that the general concept of personalized medicine can advance, and are not intended to impact adversely the ability of individual PMC members, alone or in combination, to pursue separate comments with respect to the proposed NCD on NGS for Medicare beneficiaries with advanced cancer or related issues.

Impact of Proposed Coverage Decision on Usage of NGS-based Tests for Beneficiaries with Early-Stage Breast and Ovarian Cancer

Patients benefit from having germline testing for several hereditary cancers because it increases the likelihood of identifying an explanatory gene mutation that can inform them of their risk for developing other types of cancers. Germline testing may also present opportunities for disease prevention and risk management and highlight the need for testing of family members. NGS-based germline testing can lead to improved outcomes – in part, by informing therapeutic options –for hereditary cancers like breast, ovarian, and colon cancer, all of which are prevalent among the Medicare population. Unfortunately, the proposed policy as drafted appears to deny access to testing of Medicare beneficiaries with ovarian or breast cancer, which if intended, would undermine the spirit of the draft NCD.

The proposed NCD only applies national coverage to FDA-approved or FDA-cleared NGS-based germline tests for patients with ovarian or breast cancer. There are currently no FDA-approved or FDA-cleared NGS-based germline tests for breast and ovarian cancer. This strict criterion would therefore leave Medicare beneficiaries with no covered options, despite National Comprehensive Cancer Network (NCCN) guidelines that recommend testing for some of these individuals.

The requirements would also prevent Medicare Administrative Contractors (MACs) from covering the high-quality laboratory-developed NGS-based germline tests that are available for patients with breast and ovarian cancer. PMC does not believe that CMS intended to deny patients access to these important and potentially lifesaving tests. We therefore recommend that CMS allow MACs to use their discretion to cover NGS-based tests for breast or ovarian cancer patients, including those not reviewed by the FDA, along with all other patients with a cancer diagnosis that meet the additional criteria for testing.

Finally, as a point of clarification, we ask that CMS recognize that the scope of the NCD extends beyond ovarian cancer to include epithelial ovarian, fallopian tube or primary peritoneal cancer. These cancers form in the same type of tissue and are treated the same way and, similarly, are caused by inherited gene mutations. Thus, it is important that CMS recognize these related cancers as within the scope of the NCD.

Impact of Proposed Coverage Decision on Usage of NGS-based Tests in Other Circumstances

An additional concern in the proposed NCD is the limitation on coverage for NGS-based germline tests for patients who have not been previously tested using NGS. This language prohibits coverage for any beneficiary who has had a prior NGS-based test for any reason. This new language as well as the existing similar language in the NCD for somatic testing will limit coverage for medically necessary tests in several circumstances. We believe that the final NCD should remove the prohibition on coverage for beneficiaries who have previously had an NGS-based test and allow certain cancer patients to receive both an NGS-based germline and somatic test when necessary. Additionally, a patient may need subsequent germline testing as new genes and variants are identified or in circumstances where less-invasive testing options are used.

It is not uncommon for patients to receive NGS-based somatic tests to guide cancer therapy. As an example, genetic testing for Lynch Syndrome may require a germline and somatic test in certain patients when such testing has been deemed reasonable and necessary in the context of at least one local coverage determination (LCD). An NGS-based molecular microbiology test may also be required to help diagnose an infection.

The NCD currently places a lifetime limit on coverage for the use of the same NGS-based test on a patient. Evidence is building that establishes the value of multiple NGS-based tests throughout the duration of a patient’s treatment. An NGS-based panel at the time of diagnosis simultaneously checks for multiple clinically actionable mutations that help guide physicians to targeted therapies. NCCN guidelines recommend multiplex testing such as NGS-based platforms for making treatment decisions. New mutations in many cancers are also being discovered rapidly and technology is evolving. Beneficiaries should therefore not be limited to one NGS-based test if the genes implicated in their condition were not known at the time of a previous test or were outside of the reportable range for a specific test.

A patient may also opt to have a liquid biopsy test to avoid a tissue biopsy. A negative liquid biopsy test result does not always mean that a patient is negative for a biomarker of interest and in some instances NCC guidelines dictate that the patient may require reflex tissue testing. Limiting coverage to one test per beneficiary in this situation may influence a patient’s initial choice of less-invasive testing and possibly influence a provider’s recommendation to order a follow-up tissue test.

Limiting access to one test in a patient’s lifetime could therefore prevent physicians from identifying the accurate first-line targeted therapy that may save that person’s life, and in some cases also impede access to subsequent lines of therapy. CMS should re-examine its policy on limiting the number of NGS-based tests covered per patient in light of the crucial benefits this testing allows patients and providers at diagnosis, recurrence, and/or progression of cancer.

Ensuring Future of Coverage for Applications of NGS Technology

PMC appreciates that CMS reviewed four studies on liquid biopsies at the request of PMC and other commenters. Liquid biopsies are becoming an increasingly important part of personalized medicine and the clinical management of cancer patients. We understand that the NCD does not limit coverage based on how a sample is obtained for performing a diagnostic laboratory test, and, at this time, coverage for liquid-based multi-gene sequencing panel tests will be left to a MAC’s discretion when certain patient criteria are met. CMS should continue to engage with stakeholders to ensure that beneficiaries have consistent access to liquid biopsies, with an emphasis on those tests that aid in the initial detection of targetable mutations, assist in the identification of acquired resistance mutations in patients who have relapsed on targeted therapies, and allow provider monitoring of a patient’s response to targeted therapies.

Finally, monitoring for minimal residual disease (MRD) is guideline-driven and, by definition, is an assessment that is performed more than once during a patient’s management, particularly in hematologic cancers. Local Medicare coverage is provided for use of MRD testing in some hematologic cancers, specific to those MACs participating in the MolDx program, but a wider range of cancers may require MRD assessment in the future. A rational framework for MRD utilizing NGS technology should be considered now to ensure coverage for future uses.

Conclusion

Thank you for releasing the newly proposed NCD and for considering our comments. PMC welcomes the opportunity to serve as a resource for you in continuing to shape coverage policies that impact beneficiary access to NGS technologies so that they achieve the goal we share with CMS of delivering appropriate, efficient, and accessible health care to patients.

If you have any questions about the content of this letter, please contact me at 202-589-1769 or cbens@personalizedmedicinecoalition.org.

Sincerely yours,

Cynthia A. Bens
Senior Vice President, Public Policy

CC: Joseph Chin, MD, MS
Deputy Director, Coverage and Analysis Group
Lori Ashby, MA
Director, Division of Policy & Evidence Review
Andrew Ward, PhD
Director, Evidence Development Division
Rosemarie Hakim, PhD
Senior Science Advisor, Evidence Development Division
James Rollins, MD, PhD
Medical Officer
Carl Li, MD, MPH
Medical Officer
Kimberly Long
Lead Analyst

Personalized Medicine Coalition. Comment Letter: Centers for Medicare & Medicaid Services — Proposed Medicare Coverage Decision Memorandum for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer. January 17, 2018. http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/PMC_Comments_NGS_NCD.pdf
Personalized Medicine Coalition. Comment Letter: Centers for Medicare & Medicaid Services — Proposed Medicare Coverage Decision Memorandum for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer. May 29, 2019. http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/PMC_CMS_NCD_NGS_Germline_Reconsideration.pdf

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (Reconsideration) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Director Syrek Jensen:

On behalf of the Coalition for 21st Century Medicine (C21), we appreciate the opportunity to submit comments on the Proposed Decision Memorandum (PDM) issued by the Centers for Medicare & Medicaid Services (CMS) on October 29, 2019 as part of CMS’ reconsideration of Section 90.2 of the Medicare National Coverage Determinations (NCD) Manual for testing for cancer performed on a Next Generation Sequencing (NGS) platform (CAG-00450R). C21 thanks CMS for taking stakeholder concerns into account and reconsidering the NCD for NGS; however, C21 believes that the NCD should recognize that NGS is not a single medical device with numerous indications, but a technology platform similar to Sanger or polymerase chain reaction (PCR) on which diverse clinical laboratory tests are run. Because different tests performed on an NGS platform may have no similarities to one another outside of the use of this platform, we are concerned about any framework that nationally non-covers tests based on platform alone and does not provide Medicare Administrative Contractors (MACs) with flexibility to evaluate individual NGS-based tests for coverage.

Based on this recognition of NGS as platform, we offer the following specific comments and recommended updates; recommended text edits appear in the Appendix:

• C21 supports CMS’ proposal to nationally cover FDA-cleared or approved testing for germline mutations for beneficiaries with breast and ovarian cancers (though we note that there currently are no such tests that are FDA-cleared or approved). We encourage the agency to mirror the existing NCD’s pan-cancer national coverage policy for somatic testing using NGS by expanding nationally covered indications to all FDA-cleared or approved tests for germline mutations for beneficiaries with cancer.


• C21 likewise supports the establishment of MAC discretion to cover NGS germline tests that are not FDA-cleared or approved. CMS should clarify that non-FDA cleared or approved germline tests for patients with breast and ovarian cancer may also be covered at MAC discretion, in order to avoid effectively imposing national non-coverage for these assays.


• C21 seeks clarification to the language on prior testing in the Proposed Decision to ensure that only repeat testing for the same germline content is non-covered, subject to exceptions as determined by the MACs.


• Finally, C21 urges CMS to eliminate the national non-coverage language for testing using an NGS platform in order to allow individual MACs discretion to analyze and cover new tests based on evidence in a field in which innovation is happening at a rapid pace.

C21 comprises many of the world’s most innovative diagnostic technology companies, clinical laboratories, physicians, venture capital companies, and patient advocacy groups. C21’s mission is to improve the quality of healthcare by encouraging research, development, and commercialization of innovative diagnostic technologies that will personalize patient care, improve patient outcomes, and substantially reduce healthcare costs. As such, C21 has a great interest in ensuring access to innovate clinical laboratory tests that use NGS platforms. Individual C21 members may submit independent responses and/or comments.

I. NGS is a Technology Platform

As C21 has discussed in previous comments, our support for a flexible regulatory framework for NGS testing is informed by the fact that NGS should not be thought of as a single type of test or medical device with various indications. Rather, it is a technology platform on which many different test methodologies can be performed. Testing on an NGS platform may be performed at almost any point in the cancer care continuum, including diagnosis, prognosis, treatment selection, and disease monitoring during and after treatment. NGS-based testing can be used for a wide variety of clinical indications (both cancer and non-cancer), and involve analyses of numerous different sample and biomarker types. Furthermore, NGS technology is evolving rapidly and new types of tests are being developed on or switching to the platform due to its greater efficiency and sensitivity.

For instance, in September 2018, the FDA issued a de novo authorization for the clonoSEQ assay, which uses an NGS platform not to assess mutation status (as for a FoundationOne CDx or a Guardant 360), but rather to evaluate the immune repertoire for the assessment of minimal residual disease (MRD) in patients with certain hematologic cancers.¹ In doing so, the FDA created a new test classification that is wholly distinct from the classification of NGS Oncology Mutation panels. More recently, on November 5, 2019, the FDA cleared the Sentosa SQ HIV genotyping test, which is performed on an NGS platform but otherwise has nothing to do with cancer.² As these examples demonstrate, the diverse tests performed on an NGS platform have nothing inherently in common besides the platform itself.

This reality is reflected in the approach taken by other payers and coding and clinical authorities to sequencing testing performed on different platforms. Existing coding and clinical guidelines do not distinguish between testing performed on an NGS platform and testing by means of Sanger sequencing or polymerase chain reaction (PCR). Nor did MAC coverage policies make such a distinction prior to the NCD in March 2018. We believe that in assessing whether or not to cover NGS-based tests, CMS should establish a coverage policy only for those types of tests that it has reviewed. CMS should not non-cover dissimilar tests that happen to be performed on the same sequencing platform as the tests under review. Based on this general framework, we offer the following specific comments on the PDM below.

II. Support National Coverage for FDA-Cleared or Approved Germline Tests

C21 supports CMS’ proposal to provide national coverage for FDA-cleared or approved testing for germline mutations on an NGS platform for beneficiaries with breast or ovarian cancer. We agree with the agency that “the use of NGS can identify germline mutations which can lead to better stratification of patients in the physician management of inherited cancers of the breast and ovary…suggest[ing] that NGS as a diagnostic tool can identify the germline mutations most likely to be targeted by a treatment regimen tailored to certain germline mutation[s].” We would note that at the present time there are no FDA-cleared or approved germline tests that use an NGS platform, although there is an FDA-approved germline breast/ovarian cancer test performed via Sanger sequencing.³ Nonetheless, we agree that this proposed national coverage is an appropriate “carrot” approach in anticipation of future FDA clearances or approvals from voluntary submissions of Laboratory Developed Tests (LDTs). We likewise appreciate CMS’ proposal to eliminate the stage restriction on coverage for germline testing and the requirement that the patient has decided to seek further cancer treatment, which is often inappropriate for patients with early-stage cancer.

C21, however, also recommends that the agency finalize the national coverage criteria consistent with the existing NCD by nationally covering all FDA-cleared or approved testing for germline mutations using an NGS platform, regardless of cancer type. As the agency noted in its March 16, 2018 Decision Memorandum, “FDA approval ensures that [a] device has been analytically and clinically validated,” and based on this validation, the existing NCD nationally covers FDA-cleared or approved companion diagnostics when they are indicated for use in the patient’s cancer (regardless of whether the specific indication is a companion diagnostic indication). Likewise, we believe that future FDA-cleared or approved germline tests performed on an NGS platform should be covered nationally for any cancer in which they are indicated.

III. Support MAC Discretion for Laboratory Developed Tests for Germline Mutations

C21 likewise supports the agency’s proposal to allow MAC discretion to cover tests for germline mutations using an NGS platform that are not cleared or approved by the FDA. We agree that this approach is consistent with the broad diversity of NGS-based tests for germline mutations in cancer, and with the need for regulatory flexibility to allow coverage policies for these tests to keep pace with technological innovation. C21 believes this general policy of MAC discretion should align with current MAC LCDs that allow for germline testing on an NGS platform performed by any CLIA-certified laboratory for breast, ovarian, prostate, and pancreatic cancers. With the clarifications recommended in the Appendix, the PDM’s policy of MAC discretion would allow for local coverage of these tests for patients with Stage I/II cancers. Germline testing improves patient health outcomes at this stage because it assists physicians to determine an appropriate treatment or patient management strategy before cancer reaches an advanced or metastatic stage at which treatment options are less likely to be successful.

We note that the agency’s coverage criteria for both national coverage and MAC discretion require that the patient has both “clinical indications for germline (inherited) testing” and “risk factors for germline (inherited) cancer.” The PDM does not provide guidance on how these terms are to be interpreted. Our understanding is that CMS intends for the MACs to define these terms in developing coverage policies, and we agree with this approach because it maximizes flexibility. Nonetheless, to avoid any confusion, we respectfully urge the agency to clarify in the Decision Memorandum that it intends for the MACs to interpret these coverage criteria.

C21 is concerned that, as presently drafted, the Proposed Decision’s criteria for MAC discretion proposes discretion for germline testing only for cancers other than breast and ovarian. Although the Proposed Decision would nationally cover FDA-cleared or approved NGS-based germline tests for breast and ovarian cancers, there are currently no such tests, as discussed above. Thus, the exclusion of breast and ovarian cancers from MAC discretion for germline LDTs would have the effect of nationally non-covering NGS-based germline tests for breast and ovarian cancer, which are the most commonly ordered germline tests for Medicare beneficiaries with cancer.

Such an approach would be inconsistent with and entirely counter to CMS’ rationale in the PDM that breast and ovarian are the two cancers for which the evidence of germline testing’s clinical utility is strongest. This evidence is reflected in existing clinical guidelines and MAC coverage policies. The NCCN guidelines, collectively, include criteria for germline testing for patients with breast and ovarian cancers (among others), as well as medical management recommendations for individuals found to carry a pathogenic germline mutation.⁴ For example, a woman with early-stage breast cancer who tests positive for a germline BRCA1 mutation should consider bilateral mastectomy, bilateral salpingo-oophorectomy, and ongoing surveillance with annual breast MRI for those patients who have not had bilateral masectomy, in addition to annual mammography.⁵ Notably, neither the literature nor the Guidelines distinguish between testing performed on an NGS platform and testing using other sequencing methods such as Sanger sequencing.

Based on this evidence, MACs maintain long-established coverage policies for germline tests for breast and ovarian cancer, among others.⁶ These policies cover germline tests for beneficiaries with early-stage cancer irrespective of testing platform. The Proposed Decision’s exclusion of breast and ovarian cancer from MAC discretion would eliminate this coverage in contravention of the clinical evidence. Given the absence of a reason for such an exclusion, it is our understanding that CMS did not intend to prohibit MAC discretion to cover these tests. We ask CMS to allow MACs to continue to cover germline testing for breast and ovarian cancer

IV. Request Technical Clarifications to Proposed Decision Language

C21 also respectfully requests that CMS update the language on repeat testing in the Proposed Decision. We agree that the coverage policy on repeat testing for germline mutations will, by necessity, differ from the policy in the existing NCD for somatic testing. Where somatic mutations may change over time, necessitating multiple tests in some situations, germline mutations do not.

However, the requirement for coverage or MAC discretion that a patient “not [have] been previously tested using NGS” is problematic because it is not limited to the specific NGS test. As currently written in the Proposed Decision, a beneficiary could not be covered for an NGS-based test for a germline mutation if he or she had been previously tested using any NGS-based test. For example, if a patient previously was tested using an NGS-based test for a somatic mutation that is covered under the existing NCD, the Proposed Decision would non-cover any subsequent germline test that uses NGS for that patient. Indeed, if an HIV patient took the NGS-based Sentosa SQ HIV genotyping test and then later developed cancer, the current Proposed Decision language would preclude coverage of an NGS-based germline test for that patient’s cancer based on the completely unrelated HIV test run on the same platform. Even more inconsistent, the exact same germline cancer test could be covered if it were performed on a Sanger platform. There is no clinical basis for these distinctions.

CMS should revise the repeat testing language in the Decision Memorandum to allow for national coverage of or MAC discretion to cover germline testing where the patient has not been previously tested using an NGS-based laboratory test that investigates the same germline genetic content, for the same genetic information. This would align with the repeat testing policy under consideration by MolDX,⁷ ensuring both that Medicare is not paying for duplicate germline tests and that beneficiaries are not restricted from accessing medically necessary germline testing based on unrelated prior testing that happened to have been performed on a NGS platform. We recommend leaving the establishment of any further nuances to this rule to the MACs to maximize flexibility.

Separately, we request clarification in the Decision Memo of the revised non-coverage language currently included at Appendix B of the PDM. Specifically, the non-coverage language in Section C of the proposed chapter 90.2 of the Manual still reads in a way that would non-cover tests where patients do not meet the criteria for the existing NCD. This would contradict the expanded coverage that CMS has proposed and that we encourage the agency to finalize. As discussed below, our recommendation is to eliminate the national non-coverage language entirely in order to promote MAC flexibility. However, if CMS does not take this approach, we recommend that the agency revise the non-coverage language to reflect the expanded coverage policy.

In those circumstances, we would also urge the additional changes to the non-coverage language set out in the Appendix, in order to limit provider and MAC confusion in reading the non-coverage and MAC discretion portions of the NCD. In particular, we are concerned that this confusion arises based on the order of the non-coverage and MAC discretion language, with non-coverage appearing to apply where the national coverage criteria are not met, and MAC discretion added at the end. We recommend reversing this order as shown in the Appendix below.

V. Update Proposed Decision to Address Unnecessary Coverage Limitations

Finally, in C21’s prior comment letter, we requested that the agency address other limitations on MAC discretion to cover the diversity of tests in the cancer space that use an NGS platform. National non-coverage for certain types of tests and clinical indications based on platform is inconsistent with the evidence and may stifle innovation in a fast-moving scientific field.

For instance, the limitations on repeat testing for somatic mutations in the existing NCD remain overbroad and do not address clinical indications for which repeat testing over time is necessary. Testing to evaluate MRD in patients over time is a key component of guideline-driven patient care for patients suffering from hematologic cancers, and one that requires repeated testing. The restriction of repeat testing in the existing NCD, however, continues to result in the non-coverage of subsequent MRD evaluations in contradiction of guidelines and clinical practice.

We believe that the example of MRD is illustrative of the larger concern involved in imposing broad residual non-coverage in a fast-moving biotechnology field. Given the pace of innovation in molecular diagnostics, broad non-coverage is likely to restrict access to medically necessary testing in unforeseen ways. This, in turn, will lead to multiple reconsiderations of this NCD, limiting agency resources while delaying beneficiary and physician access to useful information. C21 encourages the agency to avert this outcome by making changes in the Decision Memorandum to ensure that the MACs are allowed to keep pace with technological change. The simplest way to do this is to eliminate the national non-coverage language and allow MACs the flexibility to determine coverage policies at the local level, as they do for Sanger sequencing, PCR, and other platforms.

VI. Conclusion

C21 continues to appreciate CMS’ ongoing work to establish a national coverage policy for certain FDA-cleared or approved tests for beneficiaries with cancer when performed on an NGS platform. We believe that given the wide diversity of tests performed on an NGS platform, CMS should ensure maximum flexibility for MACs to respond to technological developments in a rapidly-changing field by eliminating the proposed national non-coverage, as well as the national non-coverage under the existing NCD. If the agency does not make that revision during this reconsideration, we respectfully request that CMS make the below technical corrections to the Proposed Decision to ensure a consistent coverage policy for germline testing.

Thank you for considering our specific comments and recommendations. Please contact me at hmurphy@c21cm.org should you have any questions or if we can provide you with further information.

Sincerely,

Hannah Murphy
Executive Director
The Coalition for 21st Century Medicine

C21 recommends the above-described revisions to the Proposed Decision to avoid inconsistency in both national coverage and MAC discretion:

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1 https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-next-generation-sequencing-basedtest-detect-very-low-levels-remaining-cancer.
2 https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-first-next-generationsequencing-test-detecting-hiv-1-drug-resistance.
3 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p140020.
4 National Comprehensive Cancer Network (NCCN) Clinical Pracitce Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Last updated Jan. 18, 2019.
5 See, e.g., National Comprehensive Cancer Network (NCCN) Clinical Pracitce Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Last updated Jan. 18, 2019; Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010 Sep 1;304(9):967-75.doi: 10.1001/jama.2010.1237. PubMed PMID: 20810374; PubMed Central PMCID: PMC2948529. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948529/pdf/ukmss-31697.pdf; Finch AP, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014 May 20;32(15):1547-53. doi: 10.1200/JCO.2013.53.2820. Epub 2014 Feb 24. PubMed PMID: 24567435; PubMed Central PMCID: PMC4026578. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026578/pdf/zlj1547.pdf; Metcalfe K, Lynch HT, Foulkes WD, et al. Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers. JAMA Oncol. 2015 Jun;1(3):306-13. doi: 10.1001/jamaoncol.2015.0658. PubMed PMID: 26181175. http://oncology.jamanetwork.com/article.aspx?articleid=2276101; Heemskerk-Gerritsen BA, Rookus MA, Aalfs CM, Ausems MG, Collée JM, Jansen L, Kets CM, Keymeulen KB, Koppert LB, Meijers-Heijboer HE, Mooij TM, Tollenaar RA, Vasen HF; HEBON, Hooning MJ, Seynaeve C. Improved overall survival after contralateral riskreducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer. 2015 Feb 1;136(3):668-77. doi: 10.1002/ijc.29032. Epub 2014 Jul 8. PubMed PMID: 24947112; Metcalfe K, Gershman S, Ghadirian P, Lynch HT, Snyder C, Tung N, Kim-Sing C, Eisen A, Foulkes WD, Rosen B, Sun P, Narod SA. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ. 2014 Feb 11;348:g226. doi: 10.1136/bmj.g226. PubMed PMID: 24519767; PubMed Central PMCID: PMC3921438
6 See Palmetto GBA: Local Coverage Determination (LCD): MolDX: BRCA1 and BRCA2 Genetic Testing (L36082), available at https://www.cms.gov/medicare-coverage-database/details/lcddetails. aspx?LCDId=36082&ver=57&SearchType=Advanced&CoverageSelection=Local&ArticleType=BC%7cSA D%7cRTC%7cReg&PolicyType=Both&s=All&KeyWord=BRCA&KeyWordLookUp=Doc&KeyWordSearchType =Exact&kq=true&bc=IAAAACAAAAAA&; Novitas Solutions, Inc: Local Coverage Determination (LCD): BRCA1 and BRCA2 Genetic Testing (L36715), available https://www.cms.gov/medicare-coveragedatabase/ details/lcddetails. aspx?LCDId=36715&ver=51&SearchType=Advanced&CoverageSelection=Local&ArticleType=Ed&Policy Type=Final&s=51&KeyWord=BRCA&KeyWordLookUp=Doc&KeyWordSearchType=Exact&kq=true&bc=IAAA ACABAAAA&; National Government Services, Inc.: Local Coverage Determination (LCD): Molecular Pathology Procedures (L35000), available at https://www.cms.gov/medicare-coveragedatabase/ details/lcddetails. aspx?LCDId=35000&ver=131&SearchType=Advanced&CoverageSelection=Local&ArticleType=SAD%7c Ed&PolicyType=Final&s=41&KeyWord=BRCA&KeyWordLookUp=Doc&KeyWordSearchType=Exact&kq=true &bc=IAAAACABAAAA&.
7 Palmetto GBA, Proposed Local Coverage Determination (LCD): MolDX: Repeat Germline Testing (DL38274), available at https://www.cms.gov/medicare-coverage-database/details/lcddetails. aspx?LCDId=38273&ContrId=377&ver=4&ContrVer=1&CntrctrSelected=377*1&Cntrctr=377&s=34&Doc Type=2%7c4%7c5&bc=AAgAAAQAAAAA&.

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November 28, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

On behalf of the American Association for Cancer Research (AACR), the first and largest scientific organization in the world dedicated to the prevention and cure of cancer through research, education, communication, and collaboration, we sincerely thank the Center for Medicare and Medicaid Services (CMS) for the opportunity to provide comments in response to the National Coverage Analysis for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. Our membership includes more than 44,000 basic, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 120 countries.

NGS tests represent an important new paradigm in diagnostic techniques for oncology. Compared to other techniques, NGS has the potential to efficiently identify significant genetic variations across nearly the entire genome, but it is important to remind ourselves that NGS is a scientific technique, a platform. When NGS tests are used as part of well-validated test protocols, this technology can help physicians elucidate clinically actionable information to guide and inform cancer treatment for patients.

The AACR commends CMS’s recognition of the importance of NGS tests and its efforts to ensure coverage of clinically and analytically valid tests. The decision summary (CAG-00450R) notes that CMS will cover FDA-approved or -cleared tests for breast or ovarian cancer patients who have not been previously tested with NGS and have risk factors for hereditary cancer, and MACs are able to determine coverage of germline NGS-tests for other cancers besides breast and ovarian if the patient has clinical indications to do so and risk factors for hereditary testing but has not been previously tested with NGS.

As described in Section VIII CMS Analysis, Summary, “The evidence for cancers of the breast and ovary suggests that the use of NGS can identify germline mutations which can lead to better stratification of patients in the physician management of inherited cancers of the breast and ovary.” The summary goes on to state, “The evidence for cancer of the breast and ovary suggests that NGS as a diagnostic tool can identify the germline mutations most likely to be targeted by a treatment regimen tailored to certain germline mutation. It is likely that the identification of such tailored treatment regimens in the clinical management of inherited cancers of the breast and ovary diagnosed by NGS will improve health outcomes of Medicare beneficiaries. Use of NGS as a diagnostic test has utility for patients in the discovery of new targeted therapies for inherited cancers and in the physician management of inherited cancers of the breast and ovary in Medicare beneficiaries. We believe that, for other cancers, the evidence is rapidly developing. We are therefore maintaining the Medicare Administrative Contractors (MACs) discretion to make coverage decisions on diagnostic uses of NGS testing for patients with inherited cancers based on new evidence that may arise.”

However, the AACR is concerned that as the decision memo is currently written and taken together with the coverage decision for somatic NGS tests in advanced cancers, this policy would not promote or ensure access to these tests but reduce access to NGS testing for patients with cancer. Therefore, we ask the agency to consider the following changes to the proposed coverage decision:

Germline Testing
Germline testing in hereditary breast and ovarian cancer patients has demonstrated clinical utility in directing clinical treatment choices, leading to better outcomes for cancer patients. However, under the criteria outlined in the proposed coverage decision, no test currently in existence qualifies for coverage. Presently, there are no FDA-approved, NGS-based, germline tests for breast or ovarian cancer. Myriad Genetics myChoice CDx and FoundationFocus CDxBRCA are FDA-approved companion diagnostics for PARP inhibitors used to treat advanced ovarian cancer. These tests can detect both germline and somatic mutations but cannot distinguish whether the mutation origination is germline or somatic. Therefore, they are not specifically indicated to detect germline mutations. The AACR recognizes that CMS may have intended this decision memo to cover such tests for germline testing, but that is not clear from the stated coverage criteria. Regardless, there are still no germline mutation tests that would meet the criteria for early-stage breast and ovarian cancer.

Furthermore, as written, the decision would prevent MACs from covering NGS-based tests for breast or ovarian cancer (because of the conditions stipulated in Section IX Conclusion, Section B). If finalized, the lack of tests that meet the national coverage criteria combined with the restrictions placed on MACs for determining coverage for breast and ovarian cancer could lead to patients not having access to highly informative and potentially lifesaving tests.

Repeat Testing
In specific circumstances, repeat NGS testing is necessary and appropriate for optimal cancer care. The proposed manual language states that to be covered for a germline test a patient must not have been “previously tested using NGS.” Similar language for somatic testing coverage may limit, if not entirely preclude, medically necessary tests from being covered. Patients may need to undergo germline testing after having already undergone somatic testing; as currently worded, this coverage determination would limit the ability of these patients to receive the testing they require. When medically necessary, cancer patients should be able to receive both somatic and germline NGS tests. In the future, disease areas outside of the oncology space may have FDA-approved NGS tests. The language in this memo could prevent the coverage of NGS-based germline testing for cancer in patients who have previously received NGS testing for other diseases. We support a coverage approach that allows patients to have subsequent testing to ensure they receive the best available therapy for their disease.

Hematologic Malignancies
Although outside the scope of the proposed germline decision memo at hand, the somatic mutation testing coverage determination (CAG-00450N) established coverage of NGS testing for patients with “recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer.” This language is not adequately inclusive of the staging systems used for hematologic malignancies. The AACR requests that the text of the final memo be updated to ensure that Medicare beneficiaries with hematologic malignancies have access to NGS-based testing. NGS tests reflect the standard of care for many such diseases and are critical to classifying them and monitoring their progress. Furthermore, research suggests that there is value in testing patients with hematologic malignancies multiple times over the course of treatment, including at diagnosis and for monitoring for progression. Such testing is often accomplished through assays for minimal residual disease (MRD), the term used to describe the small numbers of cells that remain in a patient during or after treatment. The FDA has also authorized a test for the measurement of MRD.

As cancer researchers and care providers, our goal is to ensure that cancer patients get the best available care. To that end, high-quality NGS-based testing should be available to all patients for whom clinical benefit will be obtained. As the science behind NGS tests continues to advance, increasing numbers of patients may benefit from their use. CMS should carefully consider stakeholder feedback on these and future cancer diagnostic and treatment technologies with the explicit goal to set coverage policy that supports continued innovation and ensures patient access to safe, effective, and clinically useful cancer treatments. The AACR looks forward to CMS releasing the final national coverage decision and thanks CMS for the opportunity to comment on this important issue for cancer patients.

If you have further questions, please contact Sarah K. Martin, MS, PhD, (Director, Regulatory Science and Policy) at sarah.martin@aacr.org.

Sincerely,
Margaret Foti, PhD, MD (h.c.)
Chief Executive Officer
American Association for Cancer Research

Kenneth C. Anderson, MD
Chair, Regulatory Science and Policy Subcommittee
American Association for Cancer Research

1. Jongen-Lavrencic, M, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med 2018;378: 1189-1199.
2. https://www.nejm.org/doi/full/10.1056/NEJMoa1716863
https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-next-generation-sequencing-based-test-detect-very-low-levels-remaining-cancer

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
U.S. Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori Ashby, MA
Director, Division of Policy & Evidence Review
U.S. Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Andrew Ward, PhD
Director, Evidence Development Division
U.S. Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

BIO Comments Re: Proposed National Coverage Determination for Diagnostic Laboratory Tests using Next Generation Sequencing (NGS) for Medicare Beneficiaries with Germline (Inherited) Cancer (CAG-00450R)

Dear Madam/Sir:

The Biotechnology Innovation Organization (BIO) appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’) National Coverage Determination for Diagnostic Laboratory Tests using Next Generation Sequencing (NGS) for Medicare Beneficiaries with Germline (Inherited) Cancer.

BIO is the world's largest trade association representing approximately 1,000 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO’s members develop medical products and technologies to treat patients afflicted with serious diseases, to delay the onset of these diseases, or to prevent them in the first place. Specifically, many of BIO’s members develop, market, or are impacted by diagnostic technologies for a variety of research, investigational, and clinical uses. BIO’s members also develop therapeutic products that are guided by diagnostics tests that provide the right treatment for the right patient at the right time—the essence of the modern precision medicine paradigm.

Diagnostic technologies, such as next generation sequencing (NGS) testing for cancer diagnosis and treatment, play a pivotal role in personalized medicine, allowing an individual’s genetic profile to guide decisions regarding prevention and treatment of serious health conditions. The availability of high-quality molecular profiling advances access to the most appropriate course of therapy in a more expeditious and efficient manner. Providing coverage for technologies and tools that advance patient access to the most appropriate course of treatment helps to improve health outcomes and reduce overall healthcare spending in the short- and long-term. We are appreciative of the revisions proposed by the Agency in this Proposed Decision Memorandum, which signify CMS’ recognition that germline mutations may inform treatment options and cancer risk for patients.

BIO supports CMS coverage and reimbursement for validated NGS testing as it reduces barriers to access, helps to ensure safe and effective use of medicines for patients with serious diseases to ensure they receive the highest standard of care and more personalized treatment. It is critical that as the science of cancer treatment continues to evolve, Medicare beneficiaries are able to access the full range of testing and treatments available for their given condition. High quality, validated genomic profiling assays accelerate patient access to precision approaches to diagnosing and treating cancer.

BIO appreciates that CMS has made efforts to address stakeholder concerns with the NCD’s prior language regarding clinical needs for multiple NGS tests for the same diagnosis. However, we are concerned that the revised language may inappropriately limit access to a germline NGS test for a patient who has previously received a somatic NGS test—or alternative germline NGS test—that is wholly unrelated to the advanced cancer for which this current germline NGS test is approved. The NCD currently places a lifetime limit on coverage for the use of the same NGS-based test on a patient, and we believe this limit should be removed based on the growing body of evidence that has established the value of multiple NGS tests throughout the duration of a patient’s treatment. BIO’s understanding is that it is common in clinical practice for a physician to order multiple NGS tests—including retests, confirmatory tests or repeat testing—for the same diagnosis. However, we interpret the current language to omit important coverage of multiple tests, including retests, confirmatory tests and repeat testing. BIO would urge CMS to reconsider the coverage limitations for a patient whose physician has determined additional testing is needed—when reasonable and necessary—or for whom previous NGS testing was completed for a condition related to or unrelated to the existing cancer.

BIO understands the proposed coverage requirement for NGS testing to be “FDA approved or cleared for indication for use in that patient’s cancer.” However, BIO is concerned that this limitation may lead to coverage gaps for ovarian and breast cancer patients with specific mutations that are only identified by tests that are not yet approved or cleared by the FDA. While BIO maintains longstanding support for the rigorous standards of safety and efficacy ensured by regulatory approval of NGS testing, we also appreciate that existing tests have not yet reached this benchmark. This may be problematic because CMS proposes to provide discretion to the Medicare Administrative Contractors (MACs) for coverage of NGS testing germline mutations for patients with a cancer diagnosis other than breast or ovarian. Perhaps most importantly, it is problematic that there are currently no FDA approved or cleared germline NGS tests for breast or ovarian cancer. Patients would benefit from MACs that are permitted more flexibility to analyze and cover innovative tests. Given the prospective negative impact to patients if these tests (which MACs cover today) effectively become non-covered nationally, we would encourage CMS to allow MACs to continue to provide important coverage for non-FDA approved or cleared NGS testing for patients with breast and ovarian cancer.

BIO believes this NCD is an important milestone in addressing unmet patient need in breast and ovarian cancer. Identification of mutations to deliver more targeted treatment and care can help ensure beneficiaries receive more timely access to the most appropriate treatment, improve overall health outcomes, and reduce spending on other treatments. We encourage CMS to engage with stakeholders to work through the issues identified above as well as furthering access to NGS tests in other therapeutic areas.

BIO appreciates this opportunity to comment on CMS’ National Coverage Determination. We would be pleased to provide further input or clarification of our comments, as needed, and should you have any questions about the content of this letter, please contact Jeremy Isenberg, Manager for Health Policy, at jisenberg@bio.org.

Sincerely,

/S/
Jeremy Isenberg
Manager, Health Policy
Biotechnology Innovation Organization (BIO)
www.bio.org

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Reconsideration of the National Coverage Determination on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-0045OR)

Dear Ms. Jensen,

The American Society of Hematology (ASH) is pleased to provide comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.

ASH represents more than 17,000 clinicians and scientists worldwide who are committed to the study and treatment of blood and blood-related diseases. These disorders encompass malignant hematologic disorders such as leukemia, lymphoma, and multiple myeloma, as well as non-malignant conditions such as sick cell anemia, thalassemia, bone marrow failure, venous thromboembolism, and hemophilia.

ASH appreciates CMS’ engagement with stakeholders during the reconsideration process that resulted in the release of this Proposed Decision Memo. We thank the agency for reviewing the available evidence that supports the expansion of coverage for germline testing in the current National Coverage Determination (NCD). However, we are concerned that this policy as drafted would limit, rather than expand, Medicare beneficiary access to NGS-based testing for cancer. As such, we wish to provide the following comments.

In our letter to CMS dated May 29, 2019, we stated that we were concerned about two issues impacting patients with hematologic malignancies: the restrictions placed on repeat NGS-based testing and limiting the policy to NGS-based tests for advanced cancer without special reference to hematological malignancies. We continue to have concerns after reviewing the Proposed Decision Memo, albeit repeat germline testing is not applicable in this instance.

CMS currently covers an NGS-based test in patients with “recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer.” CMS states in Section A of the Proposed Decision Memo currently open for comment that “the scope of this review is limited to next generation sequencing of germline mutations to identify patients with inherited cancer at any stage.” Hematological malignancies are not staged in the manner outlined in the somatic testing section and therefore, may not meet the agency’s definition of advanced cancer. NGS-based testing for somatic mutations is currently the standard of care in hematological malignancies and its use is likely to expand in the testing of germline mutations for these cancers as has been proposed in the referenced NCD memo. Without clarification, patients with leukemias, myelomas, and lymphomas may lose access to tests that are critical to accurate diagnosis. We respectfully request that CMS clarify that NGS-based tests for both somatic and germline mutations for hematological malignancies may be covered under the policy if it is reasonable and necessary and meets the other national or local coverage criteria.

Thank you for the opportunity to provide comments on this Proposed Decision Memo. We welcome the opportunity to discuss these comments with you and your team. If you have any questions or require further clarification, please contact Suzanne Leous, ASH’s Chief Policy Officer, at sleous@hematology.org.

Sincerely,
Roy L. Silverstein, MD
President

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November 26, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Director Syrek Jensen:

Adaptive Biotechnologies Corporation (Adaptive) is appreciative of the opportunity to comment on the proposed changes to Section 90.2 of the Medicare National Coverage Determinations (NCD) Manual for testing performed on a next generation sequencing (NGS) platform for patients with cancer (CAG-00450R). Adaptive is a commercial-stage biotech company that aims to translate the genetics of adaptive immune systems into clinical products to transform the diagnosis and treatment of disease. One clinical application of our immune medicine platform is Adaptive's clonoSEQ® Assay, an NGS-based test FDA-cleared for the detection and monitoring of minimal residual disease (MRD) in bone marrow samples from patients with B-cell acute lymphoblastic leukemia (ALL) and multiple myeloma.

As currently written, the NCD's broad non-coverage policy and structure of the NCD's coverage criteria for tests that are not nationally covered close off coverage pathways for NGS-based tests for non-advanced cancers and for applications of NGS-based tests that require multiple testing timepoints. We respectfully recommend that CMS use the current reopening of the NCD to modify the coverage framework to provide discretion for Medicare Administrative Contractor (MAC) decisions related to such tests.

As noted in our previous comments, we support the policy for national coverage of FDAauthorized companion diagnostic (CDx) NGS-based tests for treatment selection in advanced cancer patients. We also support the proposed national coverage of FDA-authorized NGS-based germline tests for use in breast and ovarian cancer patients. Both coverage policies recognize that these tests are important for delivering optimal care for Medicare beneficiaries with cancer.

We believe tests made available to Medicare beneficiaries should meet rigorous performance and evidentiary standards. We appreciate CMS's recognition of the importance of the robust analytical and clinical validation of companion diagnostic laboratory tests that undergo the FDA approval or clearance process, and we support policies that create coverage incentives for tests that obtain FDA authorization.

In the proposed memo, CMS acknowledged that "evidence is rapidly developing" and proposed maintaining MAC discretion to make coverage decisions on diagnostic uses of NGS testing based on new evidence. Reconsideration of the NCD process is lengthy and administratively burdensome, which may mean a delay in incorporating new evidence in support of the clinical utility of diagnostic tests. We fully support a path to coverage through local coverage decisions made by MACs for NGS-based cancer tests not nationally covered by the NCD. We strongly urge CMS to apply this same forward-thinking rationale to other NGS-based cancer tests that do not meet the current criteria for national coverage.

NGS is a tool, not a specific diagnostic test

NGS is a tool that can be used to characterize nucleic acid in high throughput. The characterization of nucleic acid using an NGS-based methodology has many different clinical uses, some of which are well established and standard of care. For example, NGS-based tests may examine somatic gene variants, germline gene variants, gene expression signatures, or clonal B or T cell populations. These varied readouts provide different information to inform clinical practice, such as identifying patients for whom a specific therapeutic product is safe and effective (i.e., companion diagnostic), diagnosis, detecting cancer predisposition, assessing prognosis, or assessing MRD. Therefore, the phrase "NGS as a diagnostic test" is inaccurate because NGS is not a single type of test. Rather, NGS is a technology powering many different types of tests, with varied clinical uses.

The Adaptive clonoSEQ Assay, which uses NGS to interrogate an individual patient's immune repertoire rather than to assess tumor mutational status, is just one example of this range of applications of NGS. The clonoSEQ Assay received de novo designation and authorization from FDA for detecting and monitoring MRD in bone marrow samples from patients with multiple myeloma or B-cell ALL.¹ The clonoSEQ Assay uses NGS to sequence and quantify all B-cell receptors in a sample, enabling a highly sensitive method to identify the amount of B cell cancer clones to determine how disease burden changes over time and response to treatment. With repeated testing over the course of patient care, it is necessary to track changes in disease burden and gain insights for therapeutic management for patients with hematologic cancers.

By definition and by guideline recommendations, MRD assessment is performed at more than one timepoint throughout the course of patient management. While MRD assessment for patients with a range of hematologic cancers has been covered for Medicare beneficiaries and recommended in several guidelines for many years, clonoSEQ is the first and only test available for MRD assessment in patients with certain lymphoid cancers to receive FDA authorization. Adaptive is committed to continuing to work closely with the FDA and CMS to ensure that Medicare beneficiaries with lymphoid cancers have access to robustly validated MRD assessment tools, where evidence and guidelines support their use.

We believe it is important for an NCD that governs coverage for NGS-based tests in cancer not to preclude viable pathways to coverage for this increasingly diverse set of NGS applications, where evidence and guidelines support their reasonable and necessary use. As currently written, however, the NCD's broad non-coverage policy and structure of the NCD's coverage criteria for tests that are not nationally covered close off coverage pathways for NGS-based tests for non-advanced cancers and for applications of NGS-based tests that require multiple testing timepoints.

Therefore, we respectfully recommend that CMS use the current reopening of the NCD to modify the coverage framework for MAC discretion to provide such pathways. This could be accommodated by clarifying the ability of MACs to review the analytical and clinical validation and clinical utility evidence related to NGS-based tests used in all stages of cancer and NGSbased tests that require repeat testing, and to develop rational, evidence-based coverage policies for these tests.

Specific Recommendations

Specifically, we recommend the following edits (additions are in red italics; deletions are red with strikethrough):

C. Nationally Non-Covered
Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above.

D. Other
Effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of other NGS as a NGS-based diagnostic laboratory test for patients with cancer only when the test is performed in a CLIA-certified laboratory, and ordered by a treating physician, and the patient has:

• either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and,
• either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test was performed only when a new primary cancer diagnosis is made by the treating physician; and,
• decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

Effective for services performed on or after [Month/XX] [Day/XX], [20XX], Medicare Administrative Contractors (MACs) may determine coverage of other Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when all the following conditions are met:

The patient has:

• a cancer diagnosis other than breast or ovarian cancer,
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer, and
• not been previously tested using NGS.

It is important to note that these edits do not provide national coverage to additional tests. These edits simply restore a path for NGS-based diagnostic tests to be evaluated by MACs.

We believe CMS has the responsibility to create approaches to coverage policy that keep pace with evidence generation to support innovation that improves patient care.

Sincerely,
Charles Sang
SVP, Clinical Diagnostics
Adaptive Biotechnologies

1 For more info about clonoSEQ, including test limitations, read the Technical Summary here.

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We would like to propose the following revisions to the proposed decision memo. Our recommendations are aimed at providing additional clarity.

Recommendation #1
Section I.A. of the proposed decision memo would require that a diagnostic test using NGS include “results provided to the treating physician for management of the patient using a report template to specify treatment options.”

Humana comments: We believe this criterion would benefit from specifying treatment options (i.e. pharmacotherapy) known to improve quality of life or survival. We further recommend that the NCD explicitly state that an FDA-approved companion diagnostic exists for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes used in the management of ovarian and metastatic breast cancer patients.

Recommendation #2
As currently drafted, the proposed decision demo places an emphasis on the methodology, i.e., Next Generation Sequencing, when other diagnostic laboratory tests may suffice.

Humana comments: CMS should amend the proposed decision memo to allow coverage for NGS only when somatic testing or other laboratory methods (e.g. for breast- HER2 via Immunohistochemistry or Fluorescent In Situ Hybridization) do not adequately inform pharmacotherapy decisions. We recognize that FDA-approved broad based panels (e.g. FoundationOne CDx) have been evaluated in latter stage solid tumors but their use has not been well established for early stage cancers.

Recommendation #3
The proposed decision memo is silent on the use of shared decision making.

Humana comments: We recommend that the proposed decision memo be modified to provide coverage for FDA NGS germline testing for FDA labeled indications when the beneficiary has expressed a willingness to be treated. Adding a requirement for the treating physician to obtain the explicit consent of the beneficiary will encourage shared decision making between the treating clinician and their patient.

We thank you for this opportunity to provide comments on the proposed decision memo. Please do not hesitate to contact me if you have any questions.

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RE: National Coverage Analysis (NCA) Tracking Sheet for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Administrator Verma:

The Association of Pathology Chairs represents academic departments of pathology and laboratory medicine in academic medical centers throughout the U.S. and Canada. Our members are committed to providing the best care possible, including high quality, clinically-proven Next Generation Sequencing (NGS)-based testing, when appropriate. We are concerned that the recent proposed change to the National Coverage Determination for NGS for Medicare Beneficiaries with Advanced Cancer will compromise the quality of care we are able provide to patients. Below, are comments with our specific concerns about the Proposed Decision, as written.

Point 1. Regarding “…the evidence is sufficient to expand coverage of Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory…”
Next Generation Sequencing is a method used to determine the sequence of nucleotides in a region of DNA or RNA. Newer methods of determining a genetic DNA or RNA sequence may be developed in the future that could be more effective. Also, NGS is used for non-cancer testing, such as infectious disease tests, germline genetic tests for diseases other than cancer, bone marrow engraftment analysis, and other medically important testing. We recommend specifying germline cancer risk testing using NGS technology as the focus of this Proposed Decision, or even just specifying germline cancer risk testing without specifying the method.

Point 2. Regarding “The patient has…not been previously tested using NGS”
Our understanding of the genes that can cause an inherited cancer risk is expanding. For example, inherited breast cancer risk genes began with two genes (BRCA1 and BRCA2). We now have evidence of 14 genes that cause an increased lifetime risk of breast cancer, with an additional 14 with preliminary evidence which may become clinically relevant in the future as evidence increases. This is true for many other inherited cancers by organ system. Therefore, if CMS wants to limit medically unnecessary testing using next generation sequencing methods, the Proposed Decision should not allow repeat germline testing of the same gene, unless the first test did not provide full gene sequence coverage. However, testing for genes not included in a first test, as our knowledge increases, would be considered medically necessary. We recommend coverage of multiple NGS-based tests over the course of a patient’s lifetime, as medically reasonable and necessary.

Point 3. Regarding “The diagnostic laboratory test using NGS must have all the following…Food and Drug Administration (FDA) approval or clearance…”
Since testing must be performed in a CLIA-certified laboratory, and the oversight of laboratory-developed tests remains controversial, requiring that a germline test for inherited cancer risk be FDA cleared or approved basically means that this testing will not be possible for Medicare Beneficiaries because no NGS germline inherited cancer risk tests are FDA cleared or approved. We recommend allowing CLIA regulatory standards for laboratory-developed tests to be acceptable to allow access to this testing.

Point 4. General
We encourage CMS to allow Medicare Administrative Contractors (MACs) to retain discretion to cover any germline tests for Medicare Beneficiaries with any stage of cancer that are deemed to be medically reasonable and necessary.

Thank you for this opportunity to provide comments on the National Coverage Determination for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer Proposed Decision prior to finalization. We welcome continued dialog and are available to provide more information and/or answer questions regarding this important initiative. To coordinate, please contact Priscilla Markwood, APC’s Executive Director, at pmarkwood@apcprods.org or at (302) 660-4945.

Sincerely,

Barbara Ducatman, MD
President, Association of Pathology Chairs
Chief, Pathology and Laboratory Medicine Service Line, Beaumont Health
Chair, Department of Pathology and Laboratory Medicine, Beaumont Hospital, Royal Oak
Chair, Department of Pathology, Oakland University William Beaumont School of Medicine
Physician Executive, Beaumont Medical Group

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November 27, 2019

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen:

Cleveland Clinic appreciates the opportunity to provide comments on the proposed decision memo for NGS-based testing for patients with cancer. As physicians who care for large numbers of patients with cancer, we value the efforts CMS is taking to expand coverage and allow NGS-based testing for these patients. We have some concerns about the proposed addition to the NCD and have detailed them below.

General Comments
We suggest CMS use NCCN HBOC testing criteria (rather than ACOG genetic testing criteria) to enhance patient inclusivity. Using NCCN criteria would more broadly include patients with pancreatic cancer regardless of age at diagnosis and/or family history as well as men with metastatic prostate cancer. Further, we would like to note that NGS-based testing should not be considered as a substitute for a formal genetics evaluation; NGS-based results alone may not fully inform the patient and their family of cancer risks without professional genetics-based counseling.

Exclusion of patients with previous NGS-based testing
We are concerned that a patient may be excluded for coverage of NGS-based oncology testing if they have been previously tested using this method. It is unclear if this exclusion applies to one type of NGS-based tests or all types of NGS-based tests. For example, a patient may have previously been tested using an NGS-based method for evaluation of their tumor for a somatic mutation. We do not believe that such testing should then preclude the patient from undergoing NGS-based testing for a germline mutation. A patient whose tumor is positive by NGS-based testing for a relevant somatic breast cancer variant should, following best practices, undergo germline testing (which may be done by NGS- or non-NGS-based methods) in order to understand fully the clinical ramifications for the patient and family.

It is important to stress that there may be an indication for repeat germline testing because both technology and our understanding of the relevance of genomic variants continue to evolve. The clinical relevance of more genetic loci are continually being elucidated. Thus, we suggest that CMS include a provision that allows for re-analysis of existing sequencing data as knowledge increases. We believe that repeat testing should be covered when additional implicated genes are included in new NGS-based tests that weren’t previously analyzed or when the analytic sensitivity of a clinical laboratory test has improved to allow the detection of additional clinically significant variants.

Summary: CMS should not exclude patients from NGS-based oncology testing if they have had previous NGS-based oncology testing and should leave open the possibility of coverage for reanalysis of specimens as knowledge increases. Parenthetically, it is possible such re-analysis can be done in silico (dry lab), rather than “wet lab,” i.e., less expensively.

NGS coverage for Laboratory Developed Tests (LDTs)
It is our understanding that patients will only have coverage for hereditary breast and ovarian cancer using FDA approved tests. We are unaware of FDA approved germline mutation tests for breast or ovarian cancers. We are concerned that this national coverage determination (NCD) limits LDTs to cancers other than breast and ovarian cancer. This is of concern because LDTs are widely used in clinical laboratories, have rigorous quality standards, and are widely accepted in clinical practice.

LDTs and procedures have been fundamental to patient care since the birth of molecular pathology, molecular genetics, molecular diagnostics and precision medicine. LDTs, and the laboratories that perform them, are tightly regulated by CLIA. Further, like many other laboratories, the Cleveland Clinic laboratory takes the additional step of meeting the College of American Pathologists (CAP) laboratory accreditation inspection standards, undergoing a rigorous checklist evaluation with extensive evidence of compliance. Our test validation processes (as promulgated by CAP/CLIA) are exhaustive. In Vitro Diagnostics (IVDs) are not better than LDTs. Neither are LDTs better than IVDs. They each serve the purpose for which the manufacturer (of IVDs) and provider (of LDTs) intends. They are each exhaustively validated before being offered to ordering physicians.

Summary: MACs should be given the discretion to allow coverage for LDTs for breast and ovarian cancers testing similar to the discretion provided to MACS for other cancer testing because LDT testing is tightly regulated and undergoes extensive review.

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Jeff Allen, PhD
1800 M Street NW Suite 1050 South Washington, DC 20036

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

November 28, 2019

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen,

Friends of Cancer Research (Friends) is an advocacy organization based in Washington, DC that drives collaboration among partners from every healthcare sector to power advances in science, policy, and regulation that speed life-saving treatments to patients. During the past 20 years, Friends has been instrumental in the creation and implementation of policies ensuring patients receive the best treatments in the fastest and safest way possible.

Friends was supportive of CMS’ efforts to establish uniform coverage of and beneficiary access to NGSbased tests after publication of the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)¹, and we continue to commend the agency for its recognition of the value that NGS technology provides to Medicare beneficiaries. Further, we are highly encouraged by expansion of coverage to clinical indications for germline testing included in the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R). However, we continue to be concerned that the scope of noncoverage under this coverage policy, even with this targeted expansion of coverage, will present a barrier for future application of and access to NGS technologies. Further, we believe that the national coverage determination framework, as it currently exists, is not suited to support innovation for rapidly evolving technologies like NGS.

We would like to use this comment opportunity to provide further clarification of this perspective and welcome further engagement with the Coverage and Analysis Group regarding this topic.

Limiting Noncoverage

We expressed concern in our previous comments that the broad scope of the current coverage policy, coupled with strict coverage criteria, would negatively impact innovation of NGS tests by forcing any NGS tests that do not meet the coverage criteria, such as tests for early stage cancer detection, repeat testing for disease monitoring, or tests that incorporate new biomarkers, to be non-covered. While we agree with CMS that the evidence for many of these tests may not, at this time, support a requirement for coverage, we disagree that there is sufficient evidence to support a decision of noncoverage.

Repeat Testing

Measurement of minimal residual disease (MRD) is an important component of oncology care² and the first NGS-based test to evaluate MRD has now been authorized by the FDA³. Minimal residual disease refers to a small but detectable level of cancerous cells that remain in the body following treatment, the levels of which may not be associated with physical or symptomatic signs. However, changes in MRD status can convey important information regarding a patient’s status; changes could be an indicator that a treatment is no longer working while low MRD levels without change indicates steady-state, nonprogressive disease. Given the highly specific and sensitive nature of NGS technology, it may offer improved ability to assess changes to very specific markers but will require periodic analysis. Measurement of MRD is an important tool for patient care that is denied to Medicare patients under the current coverage policy.

There are now several FDA drug labels that incorporate MRD data/evaluation across a range of hematologic cancers.⁴ Ultimately, monitoring may prove useful in solid tumors as well, with development of improved diagnostics for circulating tumor DNA (ctDNA) detected in blood samples. Circulating tumor DNA is genetic material that is shed from cancer cells and can be measured in the blood. Recent analyses have shown that changes in ctDNA levels can detect whether a tumor responds to cancer therapies, such as immune checkpoint inhibitors and targeted tyrosine kinase inhibitors^5,6,7. This is an important field of research for patient care because new markers of therapeutic response are needed. Current approaches of treatment response monitoring are limited because evaluation occurs at least 2 months post-treatment; treatment response can be assessed only in patients with measurable lesions; there exists poor interobserver reproducibility; introduction of targeted therapies modifies the correlation between efficacy and tumor shrinkage; serial radiographic imaging is expensive, time consuming, inconvenient, and adds accumulation of ionizing radiation⁸. With continued development and validation, the use of ctDNA, instead of current techniques, may ultimately alleviate many of these challenges but the potential use of ctDNA as a response monitoring tool will not be possible if coverage is limited to single testing.

Given the nascency of this technology and the fast pace of discovery in oncology, it is premature to make a determination of non-coverage for many of these tests. The use of ctDNA to monitor treatment response is an important and timely area of investigation, but it has been particularly challenging to properly investigate its role as a monitoring tool for treatment response due to variability in the way ctDNA assessment for clinical trials has been designed, the various collection methods used, and the way ctDNA changes are reported by different ctDNA assays.

Efforts are currently underway to assess the clinical validity and utility of ctDNA as a measure of response. Friends has initiated a pilot project involving several key pharmaceutical stakeholders with the objective to harmonize the use of ctDNA to MONItor Treatment Response (ctMoniTR)⁹. The pilot is currently underway and final results are expected in Spring of 2022, approximately one year after completion of this National Coverage Analysis (NCA) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R). Assuming the collective results of this and other studies support the clinical utility of ctDNA as a response monitoring tool for Medicare patients, the need to reopen this NCD may result in a cumbersome and timely process that could adversely affect access to optimal care.

Although current evidence may not yet be sufficient to conclude that coverage is necessary, the absence of evidence does not support absolute non-coverage. A policy of non-coverage represents a barrier to develop the necessary evidence and fully characterize ctDNA monitoring by NGS testing as an optimized response evaluation tool. We expect that currently pursued research will continue to generate evidence that supports the clinical use of ctDNA as a response monitoring tool; re-opening this NCD will result in a cumbersome and timely process that could adversely affect access and use of NGS testing for patient response monitoring.

Early Stage Cancers

The Medicare National Coverage Determinations Manual limits coverage of NGS-based tests when used for patients with recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer based upon an extensive review of clinical outcomes in clinical trials for NGS tests. Friends is concerned that isolating coverage to these patients will restrict access of patients with early stage or an initial diagnosis to NGS tests. As noted on page 66 of the Proposed Decision Memo (CAG-00450N)¹⁰, there is some evidence that the composition of genetic alterations in recurrent and advanced stage IV cancers may have accumulated in response to initial radiation or chemotherapy.^11,12 This may hinder a patient’s ability to receive the targeted treatment most appropriate to the genetic makeup of the individual’s cancer.

Instead, we urge CMS to consider a significantly less restrictive coverage policy that, while not necessarily requiring coverage, does not explicitly non-cover tests, such as NGS tests used for repeat testing or for early stage cancer testing as was discussed in our previous comments¹³, for which the evidence does not support non-coverage. This will enable future expansion of coverage to new NGS tests as they, an evidence supporting their clinical utility, become available while maintaining consistent patient access.

Supporting Innovation

NGS technology is an area of rapid innovation, particularly in oncology, where, because they enable testing of the entire cell genome for multiple genetic alterations simultaneously, tests are highly amenable to modifications that improve and expand on current capabilities. The fast pace of innovation that is enabled by NGS technology makes the current coverage framework utilized by CMS inappropriate, and even potentially stifling, to innovation and patient access. CMS previously acknowledged this paradigm in the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) in which coverage with evidence development (CED) was proposed, a mechanism that CMS has used previously to provide patient access to innovative technologies while the evidence needed to support coverage was being developed. Friends expressed appreciation for this intent in public comments to CMS at the time but also recognized that, while CED may be a successful model when applied to other technologies, CED was not an appropriate mechanism for evidence generation for rapidly innovative technologies like NGS¹⁴. We instead encouraged CMS to develop more adaptable coverage policies that are able to adapt and keep pace with technology and support innovation.

NGS is not the only technology being explored that exhibits transformative potential for the field of oncology but that will not fit the traditional process for determination of coverage and reimbursement. Digital pathology, for example, is an emerging field that was facilitated by the development of wholeslide imaging technology and has broad potential indications from infectious diseases to cancer. When coupled to machine learning and artificial intelligence, digital pathology has demonstrated diagnostic and prognostic applications for the treatment of cancer patients^15,16,17. The FDA issued marketing authorization for the first whole-slide imaging system (WIS) to aid in preparation and interpretation of pathology specimens, Philips IntelliSite Pathology Solution, in 2017, and the first artificial intelligence (AI)-based device to detect diabetic retinopathy in 2018, indicating that development of a device that couples digital pathology and AI as cancer diagnostic is likely not far away ^18,19. As with NGS technology, digital pathology is expected to have broad applications from diagnosis to aiding treatment decisions or as a companion diagnostic in a range of disease settings. Further, the ability to couple medical product development, such as digitization of pathology slides, to AI will most certainly lead to improvements on and expansion of indications for medical products²⁰ at exponential rates, including merging of digital pathology and NGS technologies into more comprehensive and integrated technologies. Unless more adaptive broad coverage is granted for AI-based technologies, which may not be advisable given the novelty of the technology, the rapidity of innovation and development of new evidence supporting expanded coverage for AI-based technologies will proceed well beyond the capacity of the current coverage and reimbursement frameworks to keep pace. To facilitate CMS’ commitment to supporting innovation and Medicare beneficiaries’ access to innovative products, it is of utmost importance for CMS to begin developing a more flexible coverage framework now. The coverage decision for NGS tests provides an optimal case study to work with stakeholders and progress coverage policy for innovative technologies in a thoughtful manner.

Designing an Adaptive Coverage Framework: NGS as a Case Study

A framework for coverage of innovative technologies, such as NGS tests, should balance rigorous requirements for demonstration that the technology is reasonable and necessary with continual evaluation of evidence as tests are improved and expanded. Such a framework should exhibit the following general criteria:

1. Provides national coverage to ensure consistent patient access.
2. Is flexible to evolve as technology evolves.
3. Does not pose overly burdensome reporting requirements on test developers.
4. Provides a pathway to full coverage through generation and transparency of evidence.

CMS is well-suited to design and implement an adaptive coverage framework. Specifically, CMS already has experience in implementing the Appropriate Use Criteria (AUC) framework²¹, statutorily required for determining appropriate uses to merit reimbursement for advanced diagnostic imaging tests, the agency could consider adapting the AUC framework to inform ongoing assessment of coverage. An “appropriate use for coverage” framework to enable continual evidence evaluation that informs coverage could be implemented under CMS’ authority to require evidence generation. As with the existing AUC Program, entities with expertise in diagnostic and clinical assessments could be identified for certification as Provider Led Entities (PLE). These PLEs would be qualified to develop, modify, and endorse AUC based on the submissions of a minimum set of validation standards, to demonstrate quality of individual tests, and evidentiary requirements that are necessary to support determinations of coverage for diagnostic tests and their indications. An AUC-like framework, if adapted to NGS tests, would enable ongoing assessment of current NGS technology and validation/evidentiary standards. Further, as NGS tests evolve and become increasingly sensitive and accurate, PLEs could raise evidentiary standards or validation requirements for NGS tests that must be met to qualify for or modify coverage. The CAG would, ultimately, have the ability to review PLE recommendations and amend national coverage.

An AUC-like framework to inform ongoing coverage assessments would create a coverage policy that could evolve over time along with NGS technology and would meet the four criteria for a coverage policy for innovative technologies that we have recommended.

Provides national coverage to ensure consistent patient access: A benefit of the PLE, like the local coverage determination (LCD) process, would be to enable assessment of new evidence more rapidly that national coverage determination. However, unlike LCDs, PLEs would be enabled to make coverage recommendations that would establish national coverage for Medicare patients and reduce inconsistent regional coverage to innovative new technologies, which is important to incentivize and support innovation.

Is flexible to evolve as technology evolves: PLEs could conduct intermittent evidence reviews to recommend changes to coverage requirements, including changes to validation requirements or performance standards, based upon available evidence that would allow national coverage policy to evolve as the technology evolves.

Does not pose overly burdensome reporting requirements on test developers: Well-defined and standardized real-world endpoints are when well-defined and standardized, have been shown to be readily extractable from electronic health records and claims-based databases and relevant to clinical trial endpoints for anti-PD-(L)1 therapies²². PLEs could establish criteria to inform the development of varying sources of data, such as real-world data, to supplement clinical trial data in requests for coverage.

Provides a pathway to full coverage through generation and transparency of evidence: Sponsors could submit new evidence as it becomes available to a PLE for review. The PLE could then make publicly available recommendations of expanded or amended coverage, including all evidence used to make that recommendation, to CMS without requiring reopening or establishing a new NCD.

As CMS finalizes the NCD for NGS for Medicare Beneficiaries with Advanced Cancer, we recommend convening stakeholders, including patient representatives, to develop a more flexible coverage framework that would provide adaptive coverage for innovative technologies to ensure patient access.

Conclusion

We hope that CMS will consider the recommendations made in this document and look forward to further inform discussions with the agency.

Sincerely,

Jeff Allen, PhD
President & CEO
Friends of Cancer Researc

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1 https://www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=30375&ReportType=nca 2 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 1.2014. https://www2.tri-kobe.org/nccn/guideline/hematologic/english/all.pdf
3 https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-next-generation-sequencing-based-test-detectvery-low-levels-remaining-cancer
4 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomabblincyto-amgen-inc-treatment-adult-and-pediatric
5 Raja et. al. 2018. Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab. Clin Cancer Res. 24(24):6212-6222. doi: 10.1158/1078-0432.CCR-18-0386.
6 Anagnostou et al. 2019. Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer. Cancer Res; 79(6): 1214-1225. DOI: 10.1158/0008-5472.CAN-18-1127
7 Phallen et al. 2019. Direct detection of early-stage cancers using circulating tumor DNA. Science Translational Medicine. 9(403).DOI: 10.1126/scitranslmed.aan2415
8 Garlan, F. et al. 2017. Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). Clin Cancer Res; 23(18): 5416-25. 9 https://www.focr.org/news/Friends-cancer-research-launches-ctmonitr
10 https://www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=30375&ReportType=nca
11 Meric-Bernstam F, Brusco L, Shaw K, et al. Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials. J Clin Oncol. 2015;33(25):2753-2762.
12 Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol., 2017; 18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9. PMID: 27908594.
13 https://www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=32104&ReportType=nca
14 https://www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=30375&ReportType=nca
15 Lee, G. et al. Co-occurring gland angularity in localized subgraphs: predicting biochemical recurrence in intermediate-risk prostate cancer patients. PLOS ONE 9, e97954 (2014).
16 Mungle, T. et al. MRF-ANN: a machine learning approach for automated ER scoring of breast cancer immunohistochemical images. J. Microsc. 267, 117–129 (2017).
17 Kong, J. et al. Machine-based morphologic analysis of glioblastoma using whole-slide pathology images uncovers clinically relevant molecular correlates. PLOS ONE 8, e81049 (2013).
18 https://www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-whole-slide-imagingsystem-digital-pathology
19 https://www.fda.gov/news-events/press-announcements/fda-permits-marketing-artificial-intelligence-baseddevice-detect-certain-diabetes-related-eye
20 Wang, X., et al. Computerized nuclear morphometric features from H&E slide images are prognostic of recurrence and predictive of added benefit of adjuvant chemotherapy in early stage non-small cell lung cancer. Presented at the United States and Canadian Academy of Pathology’s 108th Annual Meeting. (2019).
21 42 C.F.R. § 414.94
22 Friends of Cancer Research Whitepaper. Establishing a Framework to Evaluate Real-World Endpoints. https://www.focr.org/sites/default/files/pdf/RWE_FINAL%207.6.18.pdf Accessed Dec. 7, 2018

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Department of Health and Human Services
P.O. Box 8013
Baltimore, MD 21244–1850

RE: Comments Regarding Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen:

On behalf of AstraZeneca, I am pleased to submit comments on the proposed decision memo entitled “Next Generation Sequencing for Beneficiaries with Advanced Cancer” (CAG-00450R), dated October 29, 2019 (“proposed decision memorandum”).

AstraZeneca Pharmaceuticals LP (AstraZeneca) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas – Oncology; Cardiovascular, Renal & Metabolism; and Respiratory. We have a deep-rooted heritage in Oncology and offer a quickly growing portfolio of new medicines that has the potential to transform patients’ lives. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com.

AstraZeneca commends CMS on many of the proposed changes reflected in the proposed decision memorandum that will appropriately expand coverage of germline NGS testing in beneficiaries with cancer, regardless of stage. We also support CMS in recognizing the increasing utilization and importance of NGS testing in cancer care across both academic and community settings. However, we are concerned about specific ambiguities in the proposed decision memorandum, which we believe may continue to limit patient access to testing and disrupt clinical practices.

1. Inconsistent coverage criterion regarding repeat NGS testing could create access barriers for patients

   The conditions for coverage specified in Section 90.2 of the Medicare National Coverage Determinations (NCD) Manual that is currently applied to NGS services include a coverage criterion that only permits coverage for a patient that has “either not been previously tested using the same NGS test for the same primary diagnosis of cancer, or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician.” In the proposed decision memo, the proposed language added to the NCD coverage criterion for germline NGS testing includes a coverage criterion that the patient has “not been previously tested using NGS.” The incongruity of the retained language from the original NCD and the draft proposed language for expanded germline testing could create coverage inconsistencies involving repeat testing or use of the same test. For example, given that a somatic NGS test is not the same as a germline NGS test, according to the NCD, a patient who previously received a germline NGS test may still receive a subsequent somatic NGS test, but a person who previously received a somatic NGS test would be ineligible to receive a subsequent germline NGS test.

   Germline and somatic NGS tests provide distinct information, that are both individually and together used to inform care decisions by patients and their providers. Therefore, clarity regarding this policy language is required to minimize confusion and delay in patient access to required testing. Furthermore, we note that while there are FDA-approved or cleared NGS tests on the market that can capture germline and somatic mutations, none of them can distinguish whether a mutation is germline or somatic in the test results report. Therefore, physicians frequently have no option but to order follow-up tests to determine whether the mutation is inherited or not, which is critical to patient management (i.e., informing treatment decisions). While follow-up testing could be conducted by non-NGS methods, labs are increasingly using NGS as a test that is recognized as medically reasonable and necessary by CMS; therefore, limiting coverage of NGS tests has the potential to disrupt established lab practices.

   Additional clarity on how the existing requirements that a patient “not be tested using the same NGS test for the same primary cancer diagnosis” relates to the proposed decision memorandum restriction requiring that a patient “not be previously tested using NGS” is important to ensure access to testing is not negatively impacted. Additionally, we recommend CMS consider and provide additional clarity to address how coverage would be established for the following:

   1. Clarity on whether or not a patient who was previously tested with a somatic NGS test can receive a germline NGS, and vice versa
   2. Clarity on whether a patient that has undergone a NGS test that detects, but does not distinguish between germline and somatic mutations, can undergo a follow-up NGS test to determine whether the mutations are inherited or not

   We strongly encourage CMS to revise the proposed decision memorandum to provide explicit coverage for at least one germline and one somatic test for patients with certain advanced cancers, including those outlined in the proposed decision memorandum.

2. CMS should revise directions to local contractors to permit appropriate coverage across cancer types
   

   We are concerned that that the proposed decision memorandum for the NCD only covers FDA-approved or cleared germline NGS tests for breast and ovarian cancer and allows Medicare Administrative Contractors (MACs) to develop coverage policies for laboratory-developed tests (LDTs) only in tumor types other than breast and ovarian. Thus, there is no clear pathway for MACs to include breast and ovarian cancers for coverage of LDTs, creating potential ambiguities and concern over explicit lack of coverage for LDTs in breast and ovarian cancers. Specifically, in Appendix B of Section B of the proposed decision memorandum, CMS outlines coverage of germline NGS testing in patients with breast or ovarian cancer, but limits coverage to FDA approved or cleared tests. Section D permits Medicare Administrative Contractors (MACs) to determine coverage of tests that are not FDA-approved or cleared, but only in cancers “other than breast and ovarian cancer.” We are concerned that this policy approach could result in a lack of local coverage for NGS testing in breast and ovarian cancer. This is of particular concern as there are currently no FDA approved or cleared NGS tests for ovarian and breast cancer that can distinguish between germline and somatic mutations. This would effectively mean that a germline NGS test without FDA approval or clearance, such as an LDT NGS, that may be covered locally by a MAC in a patient with say, pancreatic cancer, will not be covered in a patient with breast or ovarian cancer, due to the criteria in Section D of Appendix B of the proposed decision memorandum.

   AstraZeneca recommends CMS remove “other than breast and ovarian cancer” from the proposed language of Section D to allow for national coverage of FDA approved and cleared NGS-based germline tests and for the MACs to develop appropriate coverage of NGS-based LDTs in breast and ovarian cancer.

AstraZeneca greatly appreciates the opportunity to provide these comments. We look forward to continued engagement with CMS and other stakeholders on this topic. If you have any questions or would like additional information on these or any other related topics, please contact me at 202-350-5542 or via e-mail at Christine.Bloomquist@astrazeneca.com.

Sincerely,

Christie Bloomquist
Vice President Corporate Affairs, North America

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COMMENTS TO CMS PROPOSED NCD FOR BREAST/OVARIAN CANCER NGS TESTING

The Centers for Medicare & Medicaid Services (“CMS”) issued the Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R) (the “Proposed NCD”) on October 29, 2019. As part of the public comment period, we submit the following comment for CMS’s consideration.

Caris MPI, Inc., doing business as Caris Life Sciences (“Caris”), is a pioneer in the advancement of next generation sequencing (“NGS”) technology and its use in personalized medicine and is a leading developer and provider of molecular profiling tests that aid physicians in determining appropriate cancer treatment for specific patients. Our laboratory, which is located in Arizona, is certified under the Clinical Laboratory Improvement Amendments of 1988 (“CLIA”), is accredited under ISO 15189:2012 and by the College of American Pathologists, and holds state clinical laboratory licenses for California, Florida, Maryland, New York, Pennsylvania, and Rhode Island.

Over the past decade, we have developed four primary NGS panels for assessing cancer tissue, one of which includes 592 genes from solid tumors using a variety of clinically validated biomarkers. Caris tests tens of thousands of tumor tissue samples per year and prepares reports to help physicians determine which therapies will produce the greatest, most durable response in patients with malignant forms of cancer, including breast and ovarian cancers. Medicare – and, in many cases, Medicaid – covers a significant number of these physician-ordered tests. However, the Proposed NCD would unnecessarily narrow already established Medicare coverage for NGS germline testing of breast or ovarian cancer cases due to the following requirements:

1. NGS testing for breast or ovarian cancer must be cleared or approved by FDA in order to receive coverage, and MACs may not determine local coverage for NGS tests for breast or ovarian cancer that are not cleared or approved by FDA; and

2. One of the requirements for coverage of NGS testing for cancer is that the patient has “not been previously tested using NGS.”

These restrictions are especially troubling because studies have shown that, among cancer patients, the population of patients with breast or ovarian cancer have the highest prevalence of germline mutations (see Kuan-lin Huang, et al., Pathogenic Germline Variants in 10,389 Adult Cancers, 173 Cell 355, 358-59 (Apr. 5, 2018)), and the Proposed NCD would limit NGS germline testing options for that population.

While we believe that conditioning coverage of NGS testing for breast and ovarian cancers on FDA approval or clearance is overly restrictive because the majority of these tests are laboratory developed tests (“LDTs”) that do not require FDA oversight, we recognize the value of using the FDA review process as a way for CMS to distinguish NGS tests and to easily categorize them. However, MACs should have the authority to determine local coverage for NGS tests for breast or ovarian cancer that are not FDA-cleared or approved when such tests are offered by CLIA-certified laboratories, are ordered by treating physicians, and meet the relevant patient requirements, particularly in light of the fact that FDA has only approved or cleared three NGS tests that include analysis of mutations relating to breast or ovarian cancer.

In addition, restricting coverage to NGS testing for patients who have “not been previously tested using NGS” is an arbitrary limitation that ignores the need to test tissue samples from patients using different gene panels (e.g., somatic vs. germline testing) based on the potential diagnosis or the type of tissue samples being analyzed or as part of treatment plan development.

Local Coverage Determinations Should Be Permitted for Non-Cleared/Approved NGS Testing for Breast and Ovarian Cancers

According to the Proposed NCD, only NGS tests for breast or ovarian cancer that meet specific criteria, including in particular those that have FDA clearance or approval, are eligible for national coverage. However, the Proposed NCD would not authorize MACs to determine local coverage for NGS tests for breast or ovarian cancer that are not FDA-cleared or approved, meaning all NGS tests for breast or ovarian cancer would need FDA clearance or approval to qualify for Medicare reimbursement.

This limitation on local coverage determinations is unjustified and appears to be inconsistent with CMS’s conclusion that the scientific studies and clinical standards it reviewed for the Proposed NCD provide sufficient evidence that NGS tests for breast or ovarian cancer will improve health outcomes of Medicare beneficiaries, which is true of all NGS tests for breast or ovarian cancer regardless of FDA clearance or approval. However, instead of allowing MACs to determine local coverage for NGS tests for breast and ovarian cancer that lack FDA clearance or approval – which can still provide significant benefits to Medicare beneficiaries according to the evidence provided in the Proposed NCD – CMS proposes to eliminate local coverage for such tests. Restricting coverage in this way would currently limit health care provider and patient choice to only three FDA-cleared or approved NGS tests that include indications for breast or ovarian cancer.

The most reasonable approach is for CMS to mimic the coverage structure described in the NGS for Advanced Cancer NCD, which (a) makes national coverage available for NGS tests for breast or ovarian cancer that meet the patient and test criteria, including obtaining FDA clearance or approval, and (b) allows NGS tests for breast or ovarian cancer that meet the patient criteria only to be eligible for local coverage, as determined by the respective MACs.

Coverage for NGS Germline Indications Should Not Be Limited to Patients Who Have Not Been Previously Tested Using NGS

The Proposed NCD states that, to be eligible for any Medicare coverage, an NGS test for breast or ovarian cancer must, among other things, have clinical indications for germline testing and must be used on a patient who has not previously undergone NGS testing of any sort. This requirement is overly restrictive as the indications and purposes of NGS testing, and even the technological aspects of and the tissues analyzed by such testing, differ based on the specific NGS test and the laboratory providing the test. Depending on design and development, NGS test panels can look for germline or somatic mutations or both. Each type of test panel is used for different purposes and, depending on the purpose, often requires analysis of specific tissues. Germline testing detects mutations that a patient has carried since birth and that exist in the genome expressed by cells in every part of the body. The patient has been living with such mutations for his/her entire life. On the other hand, tumor testing (or somatic testing) only analyzes the DNA of the tumor itself, which has mutated to be different from the native cells. While germline mutations should also be present in the tumor, it is difficult to determine if a mutation is from the germline (inherited) or is specific to the tumor when the NGS test only analyzes the genome expressed by the tumor cells.

Individual laboratories that provide NGS testing develop specific gene panels to screen against, and each test requires particular tissue samples for analysis. For example, the Praxis™ Extended RAS Panel offered by Illumina, Inc. is an NGS test that requires colorectal cancer tissue samples to identify patients who could benefit from treatment with panitumumab. CMS should not deny coverage for a patient that receives NGS testing for breast or ovarian cancer (a germline indication) simply because that patient’s colorectal tissue sample was previously tested using the Praxis™ Extended RAS Panel (a somatic indication).

Because a tumor’s DNA can differ significantly from the DNA expressed in the surrounding tissue, performing germline NGS testing on the patient’s native tissue and somatic NGS testing on a tumor tissue sample is sometimes critically necessary. For example, testing for the BRCA1 gene in a tumor and the patient’s native tissue can be an important guide for health care professionals developing the patient’s course of treatment because tumors can develop “reversion mutations” where the germline mutation is altered to make the tumor resistant to a particular therapy. Many ovarian cancer patients, following treatment with certain BRCA-targeted therapies, will develop these reversion mutations only in the tumor, rendering the drug ineffective. It is therefore critical to have both the germline and somatic results before initiating any therapy.

As an alternative, we propose limiting coverage for germline NGS testing to patients who have “not been previously tested for identical germline mutations or indications using NGS,” rather than eliminating coverage for all patients who were previously tested using NGS of any sort. This approach will provide the support and flexibility needed for health care professionals to request necessary NGS testing to develop effective treatment plans for cancer patients and for laboratories to provide such testing.

Conclusion

Caris applauds CMS efforts to expand national Medicare coverage for NGS tests to include tests for breast or ovarian cancer and determining the criteria such tests must meet before receiving national coverage or being eligible for local coverage determinations. To provide the greatest benefit to Medicare beneficiaries, however, the coverage expansion should be consistent with CMS’s previous NGS coverage determinations and extend national coverage to FDA-cleared and approved tests for breast ovarian cancer while also permitting MACs to make local coverage determinations for similar tests that are not yet cleared or approved. In addition, CMS should modify or eliminate the requirement NGS tests are only covered when the patient has not had any previous NGS testing because it severely limits health care professionals’ ability to recommend and order NGS testing necessary for cancer treatment planning and clinical laboratories’ ability to provide such critical testing.

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Reconsideration of the National Coverage Determination on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-0045OR)

Dear Ms. Jensen,

The Association for Molecular Pathology (AMP) is pleased to offer comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer, pursuant to CAG-00450R. AMP is an international medical and professional association representing approximately 2,500 physicians, doctoral scientists, and medical technologists who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government and the in vitro diagnostics industry.

AMP appreciates CMS’ engagement with the oncology community during the reconsideration process that resulted in the release of this Proposed Decision Memo. While we remain concerned about the implications of including germline testing within the scope of this National Coverage Determination (NCD), both based on the intent of the policy and evidence reviewed during its initial development¹, we thank CMS for reviewing the evidence and recognizing that it is sufficient to expand coverage. However, upon our review we have concerns that the proposed policy falls short in aligning fully with the current diagnostic landscape for germline NGS-based testing as well as the needs of Medicare beneficiaries with cancer. Below we outline our concerns as well as recommend changes to the proposed NCD language that we feel will help to provide an appropriate coverage pathway for Medicare beneficiaries. The recommended edits to the proposed policy contained within Appendix A will result in the expanded access to germline testing for patients with cancer for which CMS acknowledges sufficient evidence exists, and we urge CMS to incorporate these edits into the final policy.

The Proposed Decision Memo will restrict, not expand coverage for breast and ovarian germline tests.

As drafted, CMS would provide national coverage only for NGS-based breast and ovarian germline tests that are either FDA approved or cleared. However, there are currently no tests that meet this coverage criteria. CMS provides Medicare Administrative Contractors (MACs) discretion to cover germline NGS-based tests for cancers but excludes NGS-based tests for breast and ovarian cancer that do not meet the national coverage criteria from that coverage pathway. The MACs may interpret this to mean that they cannot otherwise cover NGS-based germline testing for breast and ovarian cancer patients. Thus, while CMS acknowledges the evidence is sufficient to expand coverage, the language as drafted has the opposite intended effect.

Within the existing NCD and the new manual language additions in the Proposed Decision Memo, CMS has bifurcated the policy to allow national coverage for FDA approved and cleared tests (given the test and the patient meet certain criteria) and MAC discretion for all other tests. AMP disagrees that FDA approved or cleared tests are the only tests that warrant national coverage for a number of reasons, including most notably that the evidence reviewed to make that determination is based on tests that are not FDA cleared or approved. While AMP would prefer that CMS expand coverage to include both non-FDA reviewed tests and those approved and cleared by the FDA, AMP sees great value in providing discretion to MACs as their ability to develop local coverage determinations (LCDs) for these tests has allowed coverage to continue and ensure there are no gaps in care. However, the proposed germline language as drafted does not achieve that and the inclusion of the language “other than breast and ovarian cancer” in the local coverage pathway prevents MACs from developing LCDs for these cancers. This mandate coupled with the fact that no FDA approved or cleared NGS-based germline tests exist for breast and ovarian cancer create a de facto non-coverage policy for germline breast or ovarian NGS-based testing. Non-coverage for germline breast or ovarian cancer would remain until the eventual development of FDA approved or cleared tests. Additionally, even if FDA were to clear or approve one test that meets CMS’s proposed coverage criteria, the policy would continue to restrict patient access by unnecessarily create a testing monopoly.

Therefore, it is important that the final NCD allow MACs to retain discretion to cover germline NGS-based tests for breast and ovarian cancer patients in order to maintain the local coverage pathway and prevent gaps in care. This will require CMS to expand the conditions under which the MACs can provide local coverage for germline testing. AMP recommends revisions to the manual in Appendix A below that would maintain national coverage for FDA approved and cleared NGS-based germline testing, while still allowing MACs to develop LCDs providing coverage for NGS-based testing for breast and ovarian cancers.

Language clarification is needed to ensure proper implementation of the proposed policy

It is critical that any additions to this NCD are drafted clearly to avoid any confusion with regards to scope and parameters for NGS-based testing for cancer. From our review, is not clear how the new language that is outlined using red font relates (or does not relate) to the existing NCD language. It is our understanding that the new language specifically relates to germline testing but that is not explicitly stated in the Proposed Decision Memo, and the new language is only delineated by date. Below, we address additional specific issues with the draft language and request edits to the Proposed Decision Memo to mitigate confusion and potentially damaging consequences.

Staging

CMS notes within Section A of the Proposed Decision Memo that “the scope of this review is limited to next generation sequencing of germline mutations to identify patients with inherited cancer at any stage.” From our review, the language in the Proposed Decision Memo includes coverage of germline testing that is inclusive of all stages, yet this is not explicitly stated in the germline section added to the proposed manual language in Appendix B, Section B. Since CMS did include language specifying the stages covered for somatic testing in the policy, we request that CMS add clarifying language to the germline language in the manual that indicates it applies to inherited cancers at any stage as indicated in Section A of the Proposed Decision Memo. Additionally, since the germline language is for cancer at any stage, the title of the NCD should be revised as it implies the policy is only for Medicare patients with advanced cancer. Within Appendix A below we have provided suggested language that is consistent with the language used to define the scope of current reconsideration.

Patient criteria redundancy

In the same section describing patient characteristics for germline testing, we found the third bullet point in Sections B and D of the proposed manual language, which addresses risk factors for germline cancer, to be redundant with the first two criteria listed. If a patient meets the other criteria in that they have cancer and clinical indications for germline testing, they, by default, possess risk factors for that inherited cancer. AMP urges that the third bullet point be struck from the proposed manual language in order to avoid confusion and eliminate redundancy when the policy is implemented.

Repeat Testing for Germline Testing

The requirement within the Proposed Decision Memo that a patient “has not been previously tested using NGS” is vague and could be interpreted very broadly, resulting in restricted patient access to medically necessary testing using NGS. At a high level, this addition as drafted potentially creates confusion as NGS-based testing is used for other clinical indications separate from cancer. For example, an NGS-based molecular microbiology test may be ordered to help diagnose an infection. As drafted, the general nature of the language could be read to mean that any Medicare beneficiary who received any NGS-based test previously for any indication could not receive germline testing to provide information on the management of their cancer.

Additionally, the stipulation with the new proposed germline language that the patient has “not been previously tested using NGS” and the lack of clarity it creates has implications for both somatic and germline NGS-based tests, most significantly for Medicare beneficiaries with cancer that may require more than one NGS-based test in order to properly diagnose and manage treatment for the patient. There are many situations in which a person is diagnosed with cancer and the oncologist orders somatic NGS- based testing. If a mutation is found that is also implicated in inherited cancers, such as a mutation in a BRCA gene, the standard practice is to refer the patient for germline testing to determine if the mutation is inherited in order to properly treat and manage the patient’s cancer. From our review of the requirement that a patient “has not been previously tested using NGS,” coverage of a germline NGS-based test in this case would not be allowed. Consequently only tests utilizing older, less-advanced, and more expensive non-NGS methods will be eligible for Medicare coverage.

Moreover, there exists a discrepancy between the language used regarding repeat testing in the indications for germline versus that for somatic testing. The provision for germline testing states that a patient has “not been previously tested using NGS”, while for somatic testing it states that a patient “has not been previously tested using the same NGS test for the same primary diagnosis of cancer, or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician.” Thus, we request that this language be revised. Our recommendation to this section, provided within Appendix A below, work to more closely mimic the language used in the somatic section of the NCD and establish limitations around repeat testing for germline that align with clinical practice needs.

Non-Coverage Provision

AMP continues to have concerns about the language in Section C of the Medicare National Coverage Determinations Manual language which outlines parameters for tests that are nationally non-covered. Similar language was removed from the original NCD when it was finalized in March 2018 after stakeholders, including AMP, commented that the proposed coverage criteria was too broad and may be construed to include diagnostic laboratory tests using NGS for conditions other than oncology.² We remain concerned about this section for the same reasons. It is unclear why the agency chose to restore Section C in this Proposed Decision Memo, and we request that CMS remove the non-coverage provisions in Section C from the final NCD.

NGS is only one specific type of sequencing methodology. CMS should review evidence and practice guidelines for clinical indications for testing, not the sequencing method.

In our comments dated May 29, 2019, we expressed our concern that providing coverage for testing based upon the technology (NGS-based), rather than for testing for the biomarker, is a fundamentally flawed construct that will require CMS to revisit this policy on a regular basis. We wish to reiterate these concerns, as we believe this construct will necessitate the need for regular reconsideration of this policy in order for it to align with clinical practice. Evidence-based guidelines from the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the American Society of Hematology, AMP, the College of American Pathologists, and the World Health Organization support the clinical utility of testing for molecular alterations in various diseases but they do not specify the specific technologies that should be utilized to detect those alterations. These groups recognize that such alterations can also be detected by non-NGS based technologies. Therefore, it would be more appropriate for a coverage policy to address the genetic alterations, cancer types, and/or targeted therapy combinations that together define clinical relevance rather than a specific methodology. AMP continues to urge CMS to adopt this approach moving forward and consider evidence that examines the underlying use of assessing certain biomarkers or genes in its assessment. As an example, a recent paper demonstrated that the results of NGS testing proficiency testing for BRAF, EGFR, and KRAS somatic mutations are equivalent or superior to that performed using other methods.³

Again, AMP thanks CMS for reconsidering this NCD based on stakeholder concerns and providing the opportunity to provide these comments. We are confident the language modifications within Appendix A will work to ensure that Medicare beneficiaries have access to medically appropriate testing. AMP is committed to working with the CMS Coverage and Analysis Group (CAG) to further modify this coverage policy to assure that patients continue to have access to clinically appropriate NGS-based testing. We look forward to working with you during this process to provide evidence and expert opinion on NGS-based testing. If you have any questions, please contact Tara Burke at tburke@amp.org.

Sincerely,

Karen E. Weck, MD, FCAP
President, Association for Molecular Pathology

Appendix A

Below, AMP provides recommended revisions to the proposed manual language. We have provided the full text of the manual language included in Appendix B of the Proposed Decision Memo for clarity. Please note that all changes are highlighted in yellow with additions to the proposed language bolded in black and any recommended deletions are noted by striking through the text.

90.2 Next Generation Sequencing (NGS) for Patients with Advanced Cancer
(Rev. 215, Issued: 04-10-19, Effective: 03-16-18, Implementation: 04-08-19)

A. General

Clinical laboratory diagnostic tests can include tests that, for example, predict the risk associated with one or more genetic variations. In addition, in vitro companion diagnostic laboratory tests provide a report of test results of genetic variations and are essential for the safe and effective use of a corresponding therapeutic product. Next Generation Sequencing (NGS) is one technique that can measure one or more genetic variations as a laboratory diagnostic test, such as when used as a companion in vitro diagnostic test.

Patients with cancer can have recurrent, relapsed, refractory, metastatic, and/or advanced stages III or IV of cancer. Clinical studies show that genetic variations in a patient’s cancer can, in concert with clinical factors, predict how each individual responds to specific treatments.

In application, a report of results of a diagnostic laboratory test using NGS (i.e., information on the cancer’s genetic variations) can contribute to predicting a patient’s response to a given drug: good, bad, or none at all. Applications of NGS to predict a patient’s response to treatment occurs ideally prior to initiation of such treatment.

B. Nationally Covered Indications

Effective for services performed on or after March 16, 2018, the Centers for Medicare & Medicaid Services (CMS) has determined that Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician, and when all of the following requirements are met:

1. Patient has:

• either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; and,
• either not been previously tested using the same NGS test for the same primary diagnosis of cancer, or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and,
• decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

2. The diagnostic laboratory test using NGS must have:

• Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,
• an FDA-approved or -cleared indication for use in that patient’s cancer; and,
• results provided to the treating physician for management of the patient using a report template to specify treatment options.

Effective for services performed on or after [Month/XX] [Day/XX], [20XX], the CMS, proposes that NGS as a diagnostic laboratory test is reasonable and necessary and covered nationally when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

The patient has:

• ovarian or breast cancer at any stage;
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer breast or ovarian cancer; and
• not been previously tested using the same germline NGS test.

The diagnostic laboratory test using NGS must have all of the following:

• FDA approval or clearance;
• an FDA approved or cleared indication for use in that patient’s cancer; and
• results provided to the treating physician for management of the patient using a report template to specify treatment options.

C. Nationally Non-Covered

Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the patient does not meet the criteria noted in section B.1. above.

D. C. Other

Effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of other NGS as a diagnostic laboratory test for patients with cancer only when the test is performed in a CLIA-certified laboratory, ordered by a treating physician, and the patient has:

• either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and,
• either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test was performed only when a new primary cancer diagnosis is made by the treating physician; and,
• decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

Effective for services performed on or after [Month/XX] [Day/XX], [20XX], Medicare Administrative Contractors (MACs) may determine coverage of other Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when all the following conditions are met:

The patient has:

• a cancer diagnosis at any stage other than breast or ovarian cancer,
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer, and
• not been previously tested using the same germline NGS test.

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1 https://www.amp.org/AMP/assets/AMP-Comments-NCDforNGSReconsideration-CAG-00450R-FINAL.pdf?pass=42
2 https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=290&NCDId=372&ncdver=1&CoverageSelection=National&KeyWord=next+generation+sequencing&KeyWordLookUp=Title&KeyWordSearchType=And&IsPopup=y&bc=AAAAAAAAQAAA&
3 Surrey, L et al. Next-Generation Sequencing (NGS) Methods Show Superior or Equivalent Performance to Non-NGS Methods on BRAF, EGFR, and KRAS Proficiency Testing Samples Arch Pathol Lab Med 2019 Aug;143(8):980-984 https://www.ncbi.nlm.nih.gov/pubmed/30865489

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Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Administrator Verma:

On behalf of the University of Pennsylvania Health System (UPHS), we appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R).

UPHS is comprised of three academic medical centers, two community hospitals and one community health system that service the city and suburbs of Philadelphia, Central Pennsylvania and Central New Jersey. Our hospitals (the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Pennsylvania Hospital, Chester County Hospital, Medical Center of Princeton and Lancaster General Hospital) provide this region with a full spectrum of health care services – from Organ Transplantation to advanced Oncology services and treatments. Combined, we provide inpatient services to over 50,000 Medicare inpatients and over 1 million Medicare outpatients on an annual basis.

UPHS is also home to the Basser Center for BRCA. The Basser Center is the first comprehensive center for the research, treatment, and prevention of BRCA-related cancers. These hereditary mutations affect both men and women and can be passed down from either parent. BRCA mutations can increase lifetime risk for cancers including breast, ovarian, pancreatic, prostate and melanoma.

Concerns with Proposed Decision Memo
Next Generation Sequencing (NGS) is a technology to read the order of nucleotide molecules on DNA and more effectively provides detailed information on multiple types of genetic alternations simultaneously. NGS oncology panel tests also provide patients and their providers a more comprehensive genetic profile of cancer and information relevant to potential cancer treatments. NGS is a type of sequencing methodology and not in itself a diagnostic test. For treatment and coverage purposes, it is critical to differentiate somatic testing from germline testing. Germline NGS-based testing is not currently approved by the FDA. However, patients who are at a great risk of cancer, including those with a family history of cancer, are eligible and generally benefit from the testing.

We appreciate CMS’ recognition that the evidence supports an expansion of coverage to NGS testing for beneficiaries with ovarian and breast cancer. However, we have concerns that the proposed policy as drafted does not fully align with the current diagnostic landscape for germline NGS-based testing as well as the needs of Medicare beneficiaries with cancer. Germline testing in patients has demonstrated clinical utility by providing treating physicians best approach treatment for patients. As we have previously commented, beneficiaries with any stage of cancer who undergo appropriate germline testing should receive coverage.

As currently drafted, CMS would provide national coverage for NGS-based breast and ovarian germline tests that are either FDA approved or cleared. As discussed above, there are currently no tests that meet this coverage criteria. As such, we would ask CMS to amend the policy to allow MACs to retain discretion to cover germline NGS-based tests for breast and ovarian cancer patients in order to maintain the local coverage pathway and prevent gaps in care.

Additionally, we would recommend that the NCD be adjusted to allow for certain cancer patients to receive both an NGS-based germline and somatic test when clinically necessary. CMS should cover multiple NGS-based tests during a patient’s lifetime, when reasonable and necessary.

Other genetic testing considerations
While outside the scope of this proposal, we encourage the agency to work with stakeholders and Congress to address genetic counseling (discussed below) and coverage for unaffecteds, or those beneficiaries with no personal history of cancer.

We understand the limitations of the agency, but also remain concerned about the exclusion of any patient testing for germline BRCA1/2 or other genes if the beneficiary does not have active cancer. Just as testing of patients with early stage disease is critical for treatment decision making, coverage for unaffected beneficiaries is important for future health management including increased screening.

As an example, the United States Preventive Services Task Force recommends that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a family history that is associated with an increased risk of a harmful mutation in one of these genes, it is not covered under Medicare. As clinicians, we are concerned that non-coverage may restrict patients’ access to medically necessary and relevant testing of germline mutations in cancer patients and will adversely impact cancer patients’ care and outcomes.

As such, we also would raise that there are other areas where changes are needed to ensure that beneficiaries at risk of hereditary cancers receive the best clinically appropriate care. Although genetic counseling is a covered benefit under Medicare, CMS does not currently recognize certified genetic counselors as healthcare providers. Providing access to certified genetic counselors would improve patient care for Medicare beneficiaries.

We look forward to working with CMS to ensure that clinically effective NGS-based testing continue to be available to all appropriate Medicare beneficiaries. We appreciate your consideration of our concerns and recommendations.

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Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

November 27, 2019

RE: Reconsideration of the National Coverage Determination on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Director Syrek Jensen:

We at Diaceutics welcome the opportunity to offer comments regarding the Centers for Medicare and Medicaid Services’ (CMS) reconsideration of the National Coverage Determination (NCD) on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. Diaceutics is a data analytics company that employs a team of experts in the field of precision medicine. We strive to assure that patients who may be eligible to receive life-saving biomarker-associated therapies receive the appropriate testing.

We are concerned over CMS’s stipulation in the proposed NCD revision that NGS testing be covered only once for a patient’s primary cancer. If this language is finalized as such, patients with somatic BRCA-positive mutations may not be covered for an NGS test if germline testing was also performed.

Numerous publications have reported the presence of somatic BRCA1 and BRCA2 mutations in ovarian cancer. It has been estimated that the prevalence of somatic mutations is somewhere between 5% and 7% of cases ¹. This implies that for every 4-5 ovarian cancer patients with a germline BRCA mutation there will be one patient with a somatic mutation. If germline BRCA1 and BRCA2 testing is performed to the exclusion of somatic BRCA testing, some patients who may be eligible for targeted therapies will be missed. This is even more important with the latest data showing PARP inhibitors in the homologous recombination deficient (HRD) and homologous recombination repair gene mutations (HRRm) patient cohorts, which by definition require both germline and somatic assessment ².

We are asking CMS to clarify that NGS testing will be covered when ordered by a physician for both germline and somatic testing on the same patient with the same primary cancer diagnosis when clinically appropriate.

Thank you for considering our specific comments and recommendations. Please contact me at jeff.schreier@diaceutics.com if you have any questions or if we can provide you with more information.

Sincerely,

Jeff Schreier
Senior Director

References
1. Frey M, Pothuri B, Homologous Recombination Deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature, Gynecologic Oncology Research and Practice, 4(2017).
2. Presidential Symposium at the 2019 European Society of Medical Oncology (ESMO) congress in Barcelona, Spain (Abstract #LBA12_PR).

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November 27, 2019

Tamara Syrek Jensen, JD
Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore MD 21244

RE: National Coverage Analysis (NCA) Tracking Sheet for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen:

The National Comprehensive Cancer Network® (NCCN®) is pleased to comment on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R) as it relates to evidence supporting the use of NGS for identification of germline mutations.

As an alliance of 28 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. NCCN’s mission is to improve and facilitate quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States. NCCN Guidelines® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives.

The NCCN Drugs & Biologics Compendium (NCCN Compendium®) has been recognized by the Centers for Medicare and Medicaid Services (CMS) and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. Further, NCCN Guidelines and Library of Compendia products are utilized by commercial payers that represent more than 85 percent of covered lives in the United States.

The NCCN Biomarkers Compendium® is a tool developed to identify the appropriate use of biomarkers to screen, diagnose, monitor, and provide predictive and prognostic information for the treatment of patients. Based directly on the NCCN Guidelines, the NCCN Biomarkers Compendium contains information designed to support decision-making around the use of biomarker testing in patients with cancer. The goal of the NCCN Biomarkers Compendium is to provide essential details for those tests which have been approved by NCCN Guidelines Panels and are recommended by the NCCN Guidelines. Tests that measure changes in genes or gene products and which are used for diagnosis, screening, monitoring, surveillance, or for providing predictive or prognostic information are included in the NCCN Biomarkers Compendium. General information on appropriate methodologies for biomarker testing is provided, focusing on the biology or abnormality being measured rather than on commercially available tests or test kits. The NCCN Biomarkers Compendium aims to ensure that patients have coverage and access to appropriate biomarker testing based on the evaluations and recommendations of NCCN Guidelines Panel members.

NCCN Evidence Base and Guidelines Development Process

The proposed decision memo inaccurately states that the NCCN Guidelines® are not evidence-based. As such, NCCN would like to provide clarifying information on our guidelines development process and the evidence-base for our guideline recommendations. The NCCN Guidelines are composed of recommendations based on the best evidence available at the time they are derived. NCCN library of guidelines contain 28,000 references to evidence. Additionally, the guidelines submitted for consideration, Genetic/Familial High-Risk Assessment Breast and Ovarian and Genetic/Familial High-Risk Assessment: Colorectal, contain respectively 508 and 255 references to evidence.

The development of the NCCN Guidelines is an ongoing and iterative process based on a critical review of the best available evidence and derivation of recommendations by a multidisciplinary panel of experts in the field of cancer. Because new data are published continuously, it is essential that the NCCN Guidelines also be continuously updated and revised to reflect new data and new clinical information. The NCCN Guidelines are reviewed and updated on a continual basis to ensure that the recommendations take into account the most current evidence. All active NCCN Guidelines are reviewed and updated at least annually. In 2018, NCCN published 185 guideline updates to ensure guidelines reflect the most up-to-date and comprehensive evidence available.

The annual review process is driven largely by the annual Institutional Review performed for each of the NCCN Guidelines. However, interim Panel meetings are conducted throughout the year, as needed, based upon new evidence from studies evaluating existing agents or regulatory approvals of new drugs or biologics that may change clinical practice standards.

Recommendations within the NCCN Guidelines are derived from critical evaluation of evidence, integrated with the clinical expertise and consensus of a multidisciplinary panel of cancer specialists, clinical experts and researchers in those situations where high-level evidence does not exist. Panels are charged with evaluating the efficacy of treatment, utility of tests or evaluations, and toxicity of the various interventions. Recommendations or changes to existing recommendations are agreed upon by Panel Members following review and discussion of the evidence during the Panel meetings. The Panel Members deliberate on the interpretation of the clinical evidence, and vote on how the evidence should be incorporated into the existing Guidelines.

NCCN Guideline References within Proposed Decision Memo

NCCN would like to emphasize the clear distinction between tumor testing for patient therapeutic guidance in our cancer specific guidelines, as opposed to germline testing noted in our Genetic/Familial High-Risk recommendations to inform risk-reduction and screening in affected individuals and their family members. Within the proposed decision memo, CMS cites submitted NCCN guidelines but lists information derived from NCCN’s Breast Cancer Guidelines and Ovarian Cancer Guidelines rather than the Genetic/Familial High-Risk Assessment Breast and Ovarian Guidelines. The NCCN Breast Cancer Guidelines and Ovarian Cancer Guidelines include treatment recommendations based on germline mutation status. However, the information contained within the current NCCN Breast Cancer Guidelines that CMS cites is not relevant to the clinical utility of NGS for germline testing, as these Guidelines provide no mention of NGS for germline mutation testing. Additionally, the information included from the NCCN Ovarian Cancer Guidelines pertains to NGS for tumor testing only. Like the breast cancer treatment guidelines, the ovarian cancer treatment guidelines provide no mention of NGS for germline mutation testing. NCCN respectfully requests that CMS refer to and consider recommendations in the Genetic/Familial High-Risk Assessment Breast and Ovarian and Genetic/Familial High-Risk Assessment: Colorectal Guidelines. In addition, NCCN respectfully requests that CMS remove the content from the treatment guidelines that are currently cited within the proposed decision memo.

Both the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal and the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend that multi-gene testing be offered in the context of professional genetic expertise, with pre- and post-test counseling being offered. When more than one gene can explain an inherited cancer syndrome, then multi-gene testing may be more efficient and/or cost-effective than single-gene testing. Besides breast and ovarian cancers, the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian also recommend consideration of multi-gene germline testing in the context of pancreatic cancer, which is thought to have a familial or hereditary component in approximately 10% of cases.^1,2

Finally, CMS does not include the submitted Genetic/Familial High-Risk Assessment: Colorectal Guidelines within this section, although it was submitted. NCCN notes that there is evidence to support germline multi-gene testing in patients with colorectal cancer in certain clinical circumstances. Examples of clinical scenarios for which multi-gene testing should be considered include:³

• Personal medical and/or family cancer history meets criteria for more than one hereditary cancer syndrome (ie, family meets both BRCA-related breast and/or ovarian cancer and Lynch Syndrome clinical criteria or family history of young onset colorectal cancer and oligopolyposis)
• Colonic polyposis with uncertain histology
• Family cancer history does not meet established testing guidelines, but consideration of inherited cancer risk persists and an appropriate panel is available
• Individuals concerned about cancer predisposition for whom family cancer history is limited or unknown
• Second-line testing for inherited cancer risk when first-line testing has been inconclusive
• Adenomatous polyposis

Clinically appropriate recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment should be used as a reference tool when understanding patient populations that would benefit from NGS tests of germline mutations. Both the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal and the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide clinical criteria, independent of the disease stage or presence of disease, for individuals with an increased genetic risk who could benefit from NGS-based quantification for hereditary cancers (Appendix 1 and Appendix 2). Once clinical criteria for multi-gene testing of germline mutations is met, the NCCN Guidelines outline specific management algorithms that might include intensive cancer surveillance, screening, or consideration of preventative medical therapies. In the proposed decision memo, CMS states that studies on colorectal cancer and Lynch syndrome were not included in the evidence review because the studies did not assess mortality. NCCN notes that timely identification of individuals at risk for hereditary cancers offers an opportunity to intervene to prevent the development of cancer which may ultimately impact mortality.

Proposed Decision Memo Language

CMS proposes to cover NGS testing for patients with ovarian or breast cancer, clinical indications for germline testing, risk factors for germline breast or ovarian cancer, who have not been previously tested using NGS. Additionally, CMS proposes to allow Medicare Administrative Contractors (MACs) to cover NGS testing when for patients with a cancer diagnosis other than breast or ovarian cancer, clinical indications for germline testing, risk factors for germline cancer other than inherited breast or ovarian cancer, and who have not been previously tested using NGS. NCCN agrees with CMS that there is evidence to support NGS testing in patients with breast and ovarian cancer. Additionally, NCCN notes there is data available to support NGS for germline testing for hereditary syndromes associated with pancreas and colon cancers.^1,2,3

NCCN has heard concerns from patient advocacy groups that the proposed decision memo as currently worded may cause confusion among providers. Specifically, the proposed decision memo states that a patient must have breast or ovarian cancer, and clinical indications for germline testing, and risk factors for germline testing. FORCE specifically notes that, for instance, all women with ovarian cancer meet clinical guidelines for germline testing. NCCN agrees with FORCE in their comments that this language may be confusing or duplicative.

NCCN has also heard concern from both providers and patient advocacy groups that as written, the proposed decision memo indicates coverage only of NGS tests that are FDA approved or cleared for germline testing. To date, none of the NGS products on the market are approved specifically for germline testing and are unable to distinguish between germline and somatic mutations. As such, NCCN agrees with the concern of patient and provider groups that this requirement may cause patient access issues.

Additionally, patient advocates have expressed concern about limiting patients to one NGS test. NCCN recommends updating the language to cover additional NGS testing when the panel incorporates new or different potentially pathogenic variants.

NCCN suggests that simplifying the NCD language will address the issues noted above and make the language more appropriate for germline testing rather than somatic testing. NCCN proposes CMS revise the NCD language to read:

A. The Centers for Medicare & Medicaid Services (CMS) proposes that the evidence is sufficient to expand coverage of Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician for management of the patient and when all the following conditions are met:

The patient has:

• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer, and
• not been previously tested using NGS, or if the proposed panel incorporates new or different potentially pathogenic variants

NCCN again appreciates the opportunity to comment on CMS’ Proposed Decision Memo for NGS for Medicare beneficiaries with advanced cancer as it relates to evidence supporting the use of NGS for identification of germline mutations. NCCN requests that CMS consider coverage consistent with nationally recognized, continuously updated, and evidence-based guidelines such as the NCCN Guidelines to ensure Medicare beneficiaries have access to the most up-to-date recommendations. Additionally, NCCN respectfully requests that CMS remove references to the Breast and Ovarian Cancer treatment guidelines and instead refer to the NCCN Genetic/Familial High-Risk Assessment Breast and Ovarian Guidelines and the NCCN Genetic/Familial High-Risk Assessment: Colorectal Guidelines. Additionally, NCCN encourages CMS to consider revised wording in the proposed decision memo that would not impede patient access to clinically appropriate germline multi-gene testing. We would welcome the opportunity to discuss our comments further and look forward to working together to ensure access to high quality, high value care for patients with cancer. Thank you for your time and consideration of our comments.

Sincerely,

Robert W. Carlson, MD
Chief Executive Officer
National Comprehensive Cancer Network

References
1. Chaffee KG, Oberg AL, McWilliams RR, et al. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. Genet Med 2018;20:119-127.
2. Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 2018;319:2401-2409.
3. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal (Version 2.2019). © 2019 National Comprehensive Cancer Network, Inc. Available at: NCCN.org. Accessed [November 2019]. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore, MD 21244

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek Jensen,

On behalf of LUNGevity Foundation, the nation’s preeminent lung cancer nonprofit that funds research, provides education and support, and builds communities for the approximately 230,000 Americans diagnosed with lung cancer each year and the 538,243 Americans living with the disease,¹ we appreciate the opportunity to submit our comments in response to the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R) that was issued on October 29, 2019.

As a leading patient advocacy group that represents the voice and interest of the national lung cancer survivor community by accelerating research to patients that is meaningful to them, empowering patients to be active participants in their care and care decisions, and helping remove barriers to access to high-quality care, LUNGevity applauds the Centers for Medicare & Medicaid Services (CMS) for providing nationwide coverage for certain NGS tests for advanced cancer through the National Coverage Determination (NCD). While the NCD has provided access to NGS for many lung cancer patients, the rapid pace of evolution of both diagnostics and therapeutics needs to be taken into account as CMS continues to evaluate the utility of NGS for advanced-stage lung cancer. In response to this most recent Proposed Decision Memo, we would like to offer comments on the following four areas:

1. Concerns about CMS’ interpretation of the NCD to non-cover NGS for patients with early stage cancers and/or when patients have a personal history of cancer.
2. Concerns about the “not previously been tested using NGS” limitation.
3. Support the proposal to preserve Medicare Administrative Contractor (MAC) discretion to cover germline testing for patients with lung cancer.
4. Request CMS to expand the scope of the existing NCD to cover multiple somatic tests for a single primary cancer during a patient’s lifetime, to ensure accurate identification of targetable mutations at diagnosis and at recurrence or progression.

Biomarker testing, typically through comprehensive genomic profiling (such as NGS) and testing for protein markers (such as PD-L1 for immunotherapy), is the first step to accessing personalized medicine. Timely access to diagnostics that inform treatment decisions is critical for all patients, especially cancer patients. In this era of unprecedented scientific advancements for the treatment of lung cancer, lung cancer patients diagnosed today have the advantage, opportunity, and right to learn about the unique biomarker profile of their cancer to help them identify the most appropriate treatment option. Our comments provided below reiterate our stand on the importance of access to timely biomarker testing, through tests such as NGS.

1. Concerns about CMS’ interpretation of the NCD to non-cover NGS for patients with early-stage cancers and/or when patients have a personal history of cancer.
LUNGevity remains concerned about CMS interpreting the NCD to non-cover NGS for patients with early-stage cancers and/or when patients have a personal history of cancer. The proposed new coverage language [in sections B.2 (for ovarian and breast cancer) and D (for other types of cancer, including lung cancer)] only require that the patient have a diagnosis of cancer, with no reference to the stage of the patient’s condition—so it would seem that early-stage patients should be covered if the criteria are otherwise met. However, the following and troublesome non-coverage language from the original NCD remains: “Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1 above.” We ask that CMS clarify their intent as the language as currently written could lead to non-coverage for patients with early-stage cancers and/or when patients have a personal history of cancer. Specifically, in Section B.1, we ask CMS to add a reference to Section D (referenced above) to clarify that patients need not have advanced lung cancer to obtain coverage.

2. Concerns about the “not previously been tested using NGS” limitation.
The language in the Proposed Decision Memo, as currently drafted, that denies coverage for individuals who have been previously tested will create a situation in which a patient who previously received somatic NGS testing would not subsequently be eligible for germline NGS testing. Somatic NGS tests provide different information than germline NGS testing, and many patients will need to receive both types of tests to develop a comprehensive understanding of their individual disease before developing a personalized treatment plan. This may especially impact patients with multiple primary lung cancers (MPLCs). With the advent of low-density computed tomography screening for lung cancer, diagnosis of MPLCs has been on the rise.² The genetic heterogeneity across MPLCs impact their treatment.³ A recent case report suggests that a differential somatic and germline NGS panel may help identify molecular characteristics of MPLC, reiterating the need for flexibility of NGS-based testing in lung cancer.⁴ We do not believe the use of restrictive language was the intent of CMS and respectfully request modification of the language to be more inclusive.

3. Support the proposal to preserve Medicare Administrative Contractor (MAC) discretion to cover germline testing for patients with lung cancer.
LUNGevity is pleased to see that CMS is proposing to allow MAC discretion regarding germline testing for patients with lung cancer. As we have discussed in previous comments, the science is evolving at an incredibly quick pace, and allowing MAC discretion regarding germline testing for patients with lung cancer offers a degree of flexibility allowing coverage decisions to be made as new evidence is collected without having to undo a National Coverage Determination. While we support this section, we encourage CMS to allow MAC discretion to cover all NGS-based germline tests for cancer patients, patients with suspected/diagnosed hematologic malignancy, and serial minimal residual disease assessments.

The role of germline mutations in lung cancer development and therapeutic interventions is evolving. The Utah cancer registry, Swedish cancer registry, and Icelandic cancer registry clearly demonstrate an increased risk of developing lung cancer (from 1.9 to 2.7 times) in individuals with a first-degree relative with lung cancer, clearly establishing a hereditary component.⁵ In recent years, largely due to our ability to conduct germline sequencing, germline mutations in actionable genes, such as EGFR and HER2, have been detected in lung cancer in non-smokers.⁶ One such mutation, EGFR T790M, currently has a matched targeted therapy (osimertinib), suggesting that it is important to include the identification of germline variants as we continue to develop more and more targeted drugs. Furthermore, identification of germline variants associated with lung cancer may help in identifying first-degree relatives who would benefit from cascade testing and subsequent lung cancer screening.⁷ Lastly, recent research from Memorial Sloan Kettering Cancer Center demonstrates that parallel tumor sequencing and somatic cell sequencing (to specifically call germline variants) is helpful in identifying tumor-specific variants.⁸ Though a single-institution effort, the study reiterates the need to include germline sequencing to further our knowledge and understanding of how these variants behave and their contribution to the development of lung cancer.

4. Request CMS to expand the scope of the existing NCD to cover multiple somatic tests for a single primary cancer during a patient’s lifetime, to ensure accurate identification of targetable mutations at diagnosis and at recurrence or progression.

Expanding the one-test-per-lifetime limit for NGS:
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, diagnosed in about 85 percent of people with lung cancer.^9-11 The complex nature of this disease requires personalized management plans for patients.¹⁰ Since the discovery of the first epidermal growth factor receptor (EGFR) mutation in lung cancer in 2004, targeted therapies have become a major component of the treatment arsenal of NSCLC patients.^11-14 At present time there are at least 20 somatic driver mutations in NSCLC that have been identified.^15,16 In concert with the identification of an increasing number of targetable mutations is the development of novel, potent, and specifically targeted therapies. Currently, FDA-approved drugs for five NSCLC mutations (EGFR, ALK, ROS1, BRAF V600E, and NTRK) are already in clinical practice, and several targeted therapies specific to other mutations are in clinical development.^17,18 Access to high-quality, timely NGS testing (at diagnosis and at recurrence or progression) is instrumental for matching patients to the appropriate targeted therapy and advancing precision medicine.

To ensure patient access to high-quality NGS testing and to ensure optimal benefits, we urge CMS to expand the scope of the existing NCD to cover multiple somatic tests for a single primary cancer during a patient’s lifetime in order to ensure accurate identification of targetable mutations at diagnosis and at recurrence or progression. New evidence clearly establishes the value of multiple NGS tests in the duration of a patient’s treatment journey. An NGS panel at the time of diagnosis and subsequent NGS panels at progression on first and subsequent lines of therapy fulfill similar and unique purposes.

NGS at diagnosis: Traditionally, before a first-line treatment decision was made for treating lung cancer patients, sequential testing for single mutations was performed. In contrast to the traditional sequential testing algorithm for EGFR followed by ALK, an NGS panel at the time of diagnosis simultaneously checks for multiple clinically actionable mutations that help guide physicians to targeted therapies to treat NSCLC.¹⁹ This, in turn, helps timely matching of the patient to the right targeted therapy should a targetable mutation be present. The National Comprehensive Cancer Network (NCCN) guidelines recommend multiplex testing such as NGS platforms for making treatment decisions.²⁰ Additionally, a multi-analyte testing approach such as NGS is tissue-sparing as against sequential single-analyte testing where each negative result leads to rapid depletion of biopsy tissue. In the case of lung cancer, this is a critical issue because multiple lung biopsies are not feasible for tissue acquisition if tissue is depleted during single-analyte testing.^21,22 The 2018 updated IASLC-CAP-AMP guidelines recommend an NGS-based platform so that tissue is conserved, patients are spared the risk of unnecessary additional biopsies, and small biopsy samples, such as fine needle aspirates, can be tested.^23-25

NGS at progression or recurrence: It is now well established that tumors evolve with time in response to targeted therapies.¹⁵ These new molecular alterations confer acquired resistance to targeted therapies and are responsible for progression or recurrence after a patient has received first-line targeted treatments. An NGS panel at the time of progression or recurrence helps identify these new mechanisms of resistance or tumor heterogeneity after treatment with a targeted agent, often independent of the original driver mutation detected at the time of diagnosis. In the recent FLAURA trial of first-line osimertinib in EGFR-positive NSCLC, NGS assays at the time of progression helped identify additional mechanisms of resistance such as mutations in the PIK3CA and the MET genes.^26,27 Currently, drugs targeting the PIK3CA and the MET genes are in clinical development, suggesting that an NGS panel is ideal for determining the next line of treatment for an NSCLC patient who has progressed on a targeted agent.

As stated above, new mutations in NSCLC are being discovered very quickly and limiting access to one test per a patient’s lifetime for a single primary cancer may be detrimental to their treatment and could both prevent their physicians from identifying the accurate first-line targeted therapy that may save their life and impede access to subsequent lines of therapy.

One of the crucial benefits of NGS testing is allowing a complete molecular profile of the patient’s tumor before first-line treatment initiation and after treatment(s), and allowing novel classes of drugs to be offered to the patient as their tumor evolves. Offering an NGS panel at the time of diagnosis and at recurrence or progression also allows for identifying driver mutations that have drugs in clinical development both as first-line treatment options and at progression or recurrence, thereby allowing patients to be enrolled rapidly in clinical trials. This is especially crucial since NCCN guidelines suggest that clinical trials may often offer the best treatment option in first- and subsequent-line settings.²⁰

LUNGevity is grateful for the opportunity to comment on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer and is eager to work with CMS to continue to ensure that patients have timely access to high-quality biomarker testing.

The recommendations outlined above can be discussed with me, my staff, and LUNGevity’s Scientific Advisory Board, which is made up of some of the world’s leading experts in lung cancer biology, practice management, access to innovative medicines, and overall patient care. I can be reached at 240-454-3100 or aeferris@lungevity.org if you have any questions or would like to engage in further dialogue. Thank you for your attention to this very important matter.

Sincerely,

Andrea Stern Ferris
President and Chief Executive Officer
LUNGevity Foundation

ABOUT LUNGEVITY FOUNDATION:
LUNGevity Foundation’s mission is to improve outcomes for people diagnosed with lung cancer. Our goals are three-fold: (1) to accelerate research to patients that is meaningful to them; (2) to empower patients to be active participants in their care and care decisions; and (3) to help remove barriers to access to high quality care. We have the largest lung cancer survivor network in the country and actively engage with them to identify, understand, and address unmet patient needs. We also have a world class Scientific Advisory Board that guides the programs and initiatives of the organization. Additionally, we collaborate with other lung cancer patient advocacy groups and organizations, such as the American Lung Association and CHEST, who serve the lung cancer community.

REFERENCES:
1. SEER. Cancer Stat Facts: Lung and Bronchus Cancer. 2019; https://seer.cancer.gov/statfacts/html/lungb.html. Accessed November 15, 2019.
2. Tanvetyanon T, Boyle TA. Clinical implications of genetic heterogeneity in multifocal pulmonary adenocarcinomas. J Thorac Dis. 2016;8(12):E1734-E1738.
3. Chen C, Huang X, Peng M, Liu W, Yu F, Wang X. Multiple primary lung cancer: a rising challenge. J Thorac Dis. 2019;11(Suppl 4):S523-S536.
4. Cytryn S, Moreira A, Chachoua A, Sabari J. Common Germline Mutations in a Patient with Multiple Primary Lung Cancers. Clinical Lung Cancer. 2019.
5. Brennan P, Hainaut P, Boffetta P. Genetics of lung-cancer susceptibility. Lancet Oncol. 2011;12(4):399-408.
6. Yamamoto H, Yatabe Y, Toyooka S. Inherited lung cancer syndromes targeting never smokers. Translational lung cancer research. 2018;7(4):498-504.
7. Koeller DR, Chen R, Oxnard G. Hereditary Lung Cancer Risk: Recent Discoveries and Implications for Genetic Counseling and Testing. Current Genetic Medicine Reports. 2018;6:6.
8. Cheng DT, Prasad M, Chekaluk Y, et al. Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC Med Genomics. 2017;10(1):33.
9. Thomas A, Liu SV, Subramaniam DS, Giaccone G. Refining the treatment of NSCLC according to histological and molecular subtypes. Nat Rev Clin Oncol. 2015;12(9):511-526.
10. Johnson DH, Schiller JH, Bunn PA, Jr. Recent clinical advances in lung cancer management. J Clin Oncol. 2014;32(10):973-982.
11. Doroshow DB, Herbst RS. Treatment of Advanced Non-Small Cell Lung Cancer in 2018. JAMA oncology. 2018;4(4):569-570.
12. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2004;350(21):2129-2139.
13. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500.
14. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311.
15. Hirsch FR, Suda K, Wiens J, Bunn PA, Jr. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016;388(10048):1012-1024.
16. Soo RA, Stone ECA, Cummings KM, et al. Scientific Advances in Thoracic Oncology 2016. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2017;12(8):1183-1209.
17. Tan WL, Jain A, Takano A, et al. Novel therapeutic targets on the horizon for lung cancer. Lancet Oncol. 2016;17(8):e347-362.
18. Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018;3(15).
19. Vnencak-Jones C, M. Berger, W. Pao. Types of Molecular Tumor Testing. . 2016; https://www.mycancergenome.org/content/molecular-medicine/types-of-molecular-tumor-testing. Accessed December 30, 2017.
20. NCCN. NCCN Guidelines Version 1.2020 Non- Small Cell Lung Cancer. 2019; https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed December November 22, 2019
21. Mascaux C, Tsao MS, Hirsch FR. Genomic Testing in Lung Cancer: Past, Present, and Future. J Natl Compr Canc Netw. 2018;16(3):323-334.
22. Longshore J. MTE20.01 Molecular Testing in Small Samples. Journal of Thoracic Oncology. 2018;13(10):S223.
23. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018;20(2):129-159.
24. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2018;13(3):323-358.
25. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346.
26. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2017:JCO2017747576.
27. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. The New England journal of medicine. 2018;378(2):113-125.

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services

Subject: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Ms. Jensen:

The American Association for Clinical Chemistry (AACC) appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) proposed national coverage determination (NCD) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.  Our association has serious concerns regarding this document and its potential adverse effects on scientific innovation and patient access to care. 

AACC is a global scientific and medical professional organization dedicated to clinical laboratory science and its application to healthcare.  AACC brings together more than 50,000 clinical laboratory professionals, physicians, research scientists, and business leaders from around the world focused on clinical chemistry, molecular diagnostics, mass spectrometry, translational medicine, lab management, and other areas of progressing laboratory science.  Since 1948, AACC has worked to advance the common interests of the field, providing programs that advance scientific collaboration, knowledge, expertise, and innovation.

CMS is proposing to only cover NGS testing for ovarian and breast cancer, if the test is either approved or cleared by the Food and Drug Administration (FDA).  We are perplexed by this recommendation given that there is no FDA cleared or approved NGS test for hereditary risk assessment of either condition on the market.  We are also concerned that this proposal, if adopted, would further limit the ability of patients to obtain appropriate, evidence-based assessment of their hereditary risk for breast or ovarian cancer.

AACC is also concerned with the agency’s decision to consider breast and ovarian cancer as if they are synonymous, since many clinical trials assess only one cancer type without the other.  It is important to note that although breast and ovarian cancer have similarities with respect to gene mutations and hereditary risk, there are important differences in how the two cancers originate and develop within individuals.  CMS should evaluate these tests separately. 

CMS also states that it would not cover NGS testing, if the patient had been previously tested with this method.  This requirement inappropriately limits somatic cancer testing.  AACC recommends that this criterion be revised.  While repeat testing of genes for hereditary risk of cancer should not be covered, NGS testing to assemble a somatic profile of a patient’s cancer is appropriate and should be covered.  Determining the molecular profile of an advanced cancer can specifically dictate treatment and several FDA-approved treatments necessitate biomarker measurement. For example, the recent approval of alpelisib in breast cancer requires documentation of an activating PIK3CA mutation, which may be measured by an NGS test. If a somatic NGS test is performed earlier in a patient’s disease progression, coverage would be restricted.

We would like to further point out that NGS is a technology that can be used for somatic profiling and hereditary cancer risk assessment, but it’s not the only method that can used. AACC recommends that this policy be modified to focus on the clinical indications with sufficient evidence for practice guidelines rather than specifying a laboratory technology. Many expert organizations have created practice guidelines that are anchored by scientific evidence.  These guidelines should be leveraged to establish the coverage policy for cancer type, genetic alteration, and treatment option.

If you have any questions, please email Vince Stine, PhD, AACC’s Senior Director of Government and Global Affairs, at vstine@aacc.org. 

Sincerely, 

/s/
David G. Grenache, PhD, DABCC
President-Elect, AACC

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Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

As a leading laboratory providing germline genetic testing services to Medicare beneficiaries, we are writing to summarize our understanding of issues regarding the CMS NCD for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer (90.2).[1] Thank you for developing the Proposed Decision Memo for public comment (CAG-00450R). Specifically, we request that CAG clarify the coverage criteria defined for a patient who has “not been previously tested using NGS.”

Ambry is concerned that the revised language would limit Medicare coverage for medically necessary laboratory testing in various circumstances. The dilemma arises due to encompassing language that appears to apply to both hereditary germline and somatic tumor testing. The criterion “not previously tested” would be triggered by any previous NGS testing whether (for example) BRCA hereditary NGS test was performed and the member is in current need of a FoundationOne™ Test. There is currently no one test that combines both germline and somatic testing, therefore Medicare recipients would fall out of coverage if tumor testing is needed, or conversely if germline is needed. Another example may be when a treating physician orders a germline cancer test using NGS technology for a beneficiary with breast cancer who previously was tested for a myeloid malignancy using NGS technology (whether covered by Medicare or not). Triggering non-coverage for any prior NGS test would be inconsistent with the intent of the coverage determination and deny needed diagnostics for Medicare recipients who meet medical necessity for testing. Finally, Medicare should consider the ongoing migration of molecular testing to an NGS platform. In this circumstance (for example the MammaPrint™ test or the FDA-approved Sensa HIV test) the new coverage would be unavailable to the Medicare patient since there was a prior NGS-based test. We do not believe that this was the intent of the CAG in its latest iteration.

The MolDx program has developed an LCD with language that may address CAG’s concerns in this regard. MolDx LCD “Repeat Germline Testing” (DL38353)[2] contains language that can address the reasonable concerns about duplicative testing while allowing for appropriate use of NGS where the gene of current interest or target (somatic/tumor vs. germline) has not been previously tested. This language may be useful in this NCD:

“This contractor does not consider any laboratory test that investigates the same germline genetic content, for the same genetic information, that has already been tested in the same Medicare beneficiary to be reasonable or necessary.

Germline testing using gene panels that contain some genetic content that has already been tested in the same Medicare beneficiary may be considered reasonable and necessary provided that there is established clinical utility present in the remaining, non-duplicative genetic components of the test. Unit of Service (UOS) for any one specific germline DNA or RNA-based test is limited to one per lifetime. Examples of germline tests include (but are not limited to) single gene and gene panel tests for: hereditary cancer syndromes or cancer predisposition, inherited disorders, and pharmacogenomics/cytochrome P450 testing,...”

We ask that you consider these clinical scenarios and therefore clearly define any rules based on previous NGS testing in the final revision. By doing so, clinical practice will align with the intended coverage, so that Medicare recipients receive reasonable and necessary care.

As a laboratory leading the way in hereditary germline testing and that has provided actionable clinical results for thousands of Medicare recipients, we thank you for your consideration of these comments

Sincerely,

Ambry Genetics

[1] National Coverage Analysis (NCA) Tracking Sheet for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R), available at https://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx?NCAId=296&bc=ACAAAAAAQAAA&.

[2] MolDX: Repeat Germline Testing (DL38353) https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=38352&ContrId=351&ver=7&ContrVer=1&CntrctrSelected=351*1&Cntrctr=351&DocType=7&bc=AAACAAQAAAAA&

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November 25, 2019

Mrs. Seema Verma, Administrator
Centers for Medicare and Medicaid Services (CMS)
200 Independence Avenue, SW
Washington, DC 20201

Subject: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R), October 29, 2019.

Dear Administrator Verma,

On behalf of the Bladder Cancer Advocacy Network (BCAN), the only national organization solely devoted to advancing bladder cancer research and supporting those affected by the disease, I am writing to share our concerns that the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R) would greatly limit access to Medicare coverage for genetic testing of hereditary cancer using NGS. At a time when scientific advances are developing better and more focused technologies that will help us identify and treat cancer at its earliest stages, its critical that CMS works to expand, not limit, the path for research and treatment.

The final decision that CMS makes, regarding NGS genetic testing coverage, must ensure that Medicare patients are not limited in their access to high quality genetic testing as this testing is critical to informing prevention and influencing personalized treatment when cancer develops.

We were pleased to see that the memo proposes to cover germline (i.e. hereditary) tests that use next generation sequencing for patients with any stage of cancer who are at risk for an inherited cancer syndrome either through the national coverage determination or through the discretion of local and regional Medicare administrators. This proposal has the potential to positively and directly impact the millions of people across our country who have had cancer touch their lives.

While the proposal has great promise, we are deeply concerned that the memo also would do two things that would restrict patient access to this critical genetic testing. First, the memo proposes that coverage only be granted to FDA-approved or cleared hereditary breast and ovarian cancer (HBOC) testing. This would limit coverage because there are currently no FDA-approved or cleared NGS tests for breast and ovarian cancer. As written, this would put Medicare patients in a Catch 22 situation because no testing meets the regulatory requirements for coverage, even though CMS acknowledges the benefits of testing for HBOC. While HBOC’s are treated this way, all other types of hereditary cancer are left to the local discretion of Medicare Administrative Contractors (MACs) and are not required to be FDA-approved or cleared. We urge you to correct this disparity and ensure that HBOCs are treated like all other cancers.

In addition, the memo proposes no coverage for any repeat NGS-based testing, regardless of clinical indication. Because NGS testing can be used across many health conditions and is used to assess both inherited (germline) and acquired (somatic) mutations in cancer, this would greatly restrict the use of genetic testing. As currently written, if a patent has had an NGS test of their inherited/germline risk, they would be denied coverage for any other NGS tests, such as NGS-based somatic tests for tumor mutations to guide therapy of a cancer, an NGS molecular microbiology test to help diagnose an infection or an NGS test for a different or unrelated health condition. Through this memo, CMS clearly recognizes the need to provide coverage to NGS-based genetic testing for Medicare beneficiaries battling cancer. While we are appreciative of this important recognition, the bladder cancer community strongly urges CMS to correct the current the draft memo to ensure that the agency can truly meet its coverage goals as outlined in the memo.

To achieve this goal, we ask CMS to correct and improve the draft memo in the following ways. First, allow coverage for the high-quality CLIA- and CAP-regulated laboratory developed tests (LDTs) that currently are available to patients either directly through CMS or via local MAC discretion. Secondly, remove the restriction on repeat NGS testing and/or clarify that the restriction is for one clinical indication. Should CMS wish to provide a coverage limit, that limit should focus on the purpose of the test, not the technology platform on which it was performed. Finally, CMS should specifically allow local coverage decisions by MACs for NGS testing in all hereditary cancers, including HBOC.

On behalf of the Bladder Cancer Advocacy Network, and the millions of Americans who have been directly or indirectly touched by bladder cancer, we would like to thank CMS for its recognition of the importance and need to expand NGS coverage and request that CMS amend the memo to include the additional protections that we have outlined in these comments. With these clarifications, we believe the new and continued coverages proposed will go a long way in not only preventing the onset of cancer but help to inform the treatment of patients with cancer across our country.

Sincerely,

Andrea Maddox-Smith, CEO
The Bladder Cancer Advocacy Network (BCAN)

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November 26, 2019

Tamara Syrek Jensen, J.D.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen,

The College of American Pathologists (CAP) appreciates the opportunity to submit comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R).

As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the CAP serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. Members of the CAP are experts in molecular pathology and the CAP works to ensure that Medicare beneficiaries have access to tests that help guide clinical diagnosis and care delivered to Medicare beneficiaries.

We thank the Centers for Medicare & Medicaid Services’ (CMS) for recognizing the vital importance of expanding coverage of NGS testing methodologies to earlier stage cancers in patients whose inherited DNA variations may put them at risk for developing breast and ovarian cancer. The CAP supports CMS’ proposal to guarantee national coverage for FDA approved/cleared tests and to allow Medicare Administrative Contractors (MACs) discretion to cover other NGS-based tests, regardless of cancer stage. However, we remain concerned about several aspects of the proposed changes that, if implemented, would continue to restrict patient access to early stage germline testing and we urge CMS to make the following outlined changes:

Coverage requirements for breast and ovarian cancers

Under the proposed language, patients with hereditary breast and ovarian cancer may receive national coverage only for FDA approved tests. However, there are currently no FDA approved or cleared germline gene mutation tests for breast or ovarian cancers. Furthermore, CMS proposes to allow MACs discretion to determine coverage of other clinical laboratory tests using NGS-based methods when a patient has a cancer diagnosis other than (emphasis added) breast or ovarian cancer.” The FDA approval requirement excludes coverage for all available non-FDA approved/cleared tests that use NGS-based methods, regardless of how their performance compared to other non-NGS methods used for similar testing. By this standard, all coverage for germline testing is essentially denied for patients with early stage breast and ovarian cancers. Restricting payment for testing in this way would be a grievous error.

We request that CMS remove “other than breast or ovarian cancer” and allow MACs to determine coverage for ALL types of cancers, including breast and ovarian, when the evidence is sufficient and when tests meet the other coverage criteria outlined in the NCD.

One test per patient requirement

A. One of the proposed requirements for coverage is that a patient has “not been previously tested using NGS.” It is unclear from this statement if this refers to just one method of testing using NGS technology, or if it applies to all testing methods using NGS. For example, the implication is that, if a patient has had a somatic NGS-based test like EGFR and KRAS, it would preclude a germline NGS-based test for BRCA.

We request that CMS replace the proposed coverage criteria that states: “not been previously tested using NGS” with, “not been previously testing using the same NGS-based test for the same primary cancer diagnosis.”

B. While repeated testing of an individual's genome for inherited diseases is generally not reasonable and necessary, rapid gains in methodology and gene data base have demonstrated the need for some repeat germline testing for hereditary breast cancer. For example, inherited breast cancer tests used to only examine BRCA1 and 2, but use of a larger cancer panel has increased the diagnostic rate significantly from 2.5% (BRCA1/2 alone) to 6.3% using a guideline panel (11 genes) and 9.4% using a large cancer panel (80 genes) in a cohort of 959 patients (Beitsch et al. 2019).

Further modifications to protocols, techniques and instruments for NGS continue to provide significant improvements in the detection of germline variants associated with inherited cancer today compared to earlier tests. As expanded panel tests become more widely adopted it is imperative that CMS keep pace to reflect quality health care for Medicare beneficiaries.

We request that CMS allow for repeat germline testing when additional implicated genes are included in a test; when the reportable range in genes already tested has been expanded to encompass pathogenic variants for which there is sufficient evidence for clinical testing; or when the analytic sensitivity has improved since the time of the previous test to allow the detection of difficult variants such as mosaic variants, copy number variants or triplet repeat alleles.

Cancer Stage

The Proposed Decision Memo states CMS’ intention to cover NGS based technology for germline testing in breast and ovarian regardless of stage, yet the proposed changes to Sections B.2. “Nationally Covered Indications” and Section D “Other”, make no reference to cancer stage. Additionally, the NCD title causes further confusion by referring only to Medicare beneficiaries with advanced cancer.

To avoid confusion, we request that the final NCD be modified to reflect coverage for NGS-based germline testing for breast and ovarian cancer regardless of the patient’s cancer stage. Additionally, we urge CMS to retitle the NCD to more accurately reflect the new revised policy.

Thank you again for the opportunity to provide comments on the proposed changes to the NCD. We appreciate CMS’ ongoing commitment to ensure that Medicare beneficiaries with cancer have access to clinically indicated testing for both tumor and germline mutations.

Please contact Nonda Wilson nwilson@cap.org with any questions regarding these comments or if we can provide additional information to CMS on this important national coverage determination.

References

1.Beitsch, P.D., et al., Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J Clin Oncol, 2019. 37(6): p. 453-460.

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November 26, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, Maryland 21244
Tamara.Syrekjensen@cms.hhs.gov
Kimberly.Long@cms.hhs.gov

Seema Verma
Administrator
Centers for Medicare & Medicaid Services
200 Independence Avenue, SW
Washington, DC 20201
Seema.Verma@cms.hhs.gov

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Director Jensen:

Thank you for the opportunity to submit comments on behalf of our organizations and the millions of Americans we represent. We are very pleased to see that CMS has heard the concerns of the patient and health care provider community and is making efforts to broaden and further define coverage for NGS-based germline testing.

A. Coverage of NGS Testing in Breast and Ovarian Cancer

In Section A of the Proposed Decision Memo, CMS states that the evidence is sufficient to expand coverage of NGS as a diagnostic laboratory test when the patient has:

• ovarian or breast cancer;
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) breast or ovarian cancer; and
• not been previously tested using NGS.

The proposed policy also stipulates that the diagnostic laboratory test using NGS must have all of the following:

• Food and Drug Administration (FDA) approval or clearance;
• an FDA approved or cleared indication for use in that patient's cancer; and
• results provided to the treating physician for management of the patient using a report template to specify treatment options.

We have a number of concerns with this proposed NCD language:

• Requirement for both "Clinical indications for germline (inherited) testing" and "risk factors for germline (inherited) breast or ovarian cancer".
  

  The stipulation that the patient has a diagnosis of ovarian and breast cancer, "clinical indications" and "risk factors" for germline testing and breast or ovarian cancer is duplicative and somewhat ambiguous. For instance, all women with ovarian cancer meet clinical guidelines for germline testing. What additional risk factors must be present to qualify for germline testing? Is a known mutation in the family considered a risk factor? It may be difficult for a clinician to provide evidence of clinical indications and risk factors as these terms can be synonymous.

  Suggested Clarification:
  

  To avoid confusion, we recommend that CMS clarify its definition of clinical indications and risk factors. NCCN provides comprehensive recommendations on the appropriate testing of cancer patients. The agency should refer to NCCN for guidance. CMS might also provide examples of clinical indications and risk factors, and revise the language to read:

  CMS proposes that the evidence is sufficient to expand coverage of NGS as a diagnostic laboratory test when the patient has:

  • Ovarian cancer; or
  • Breast cancer, and clinical indications for germline genetic testing including personal or family medical history consistent with an inherited mutation

• FDA approval or clearance of the diagnostic laboratory test.
  

  To our knowledge, there are no FDA-approved or -cleared NGS tests for germline testing in solid tumor cancers. Of the FDA-cleared or -approved NGS diagnostic tests, none specifically detect germline mutations via NGS technology.

  • F1CDx cannot distinguish between germline and somatic mutations.¹ If the test finds a BRCA1/2 mutation, it is unable to determine whether that mutation is germline or somatic. Therefore, the patient must undergo a subsequent germline test.
  • myChoice "identifies germline and somatic variants in the tumor but does not distinguish between the two."² Like F1CDx, additional testing is needed if a germline mutation is suspected.
  • MSK-IMPACT "is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability."³ It is not a germline test.

  Current FDA-approved germline tests use non-NGS technology (predominantly Sanger sequencing). For example, BRACAnalysis CDx is FDA-approved for germline testing of BRCA1/2 mutations in conjunction with olaparib treatment for advanced or metastatic breast cancer; it is a Sanger sequencing test.

  Without an FDA-cleared or approved NGS-based germline test for breast and ovarian cancer, NGS-based germline testing remains non-covered at the national level.

  The CMS analysis "includes peer-reviewed, published clinical studies, and guidelines pertaining to using NGS as a diagnostic test to identify germline mutations in the diagnosis of inherited cancers." Ultimately, CMS concludes, "[a]s a result of current evidence and our present analysis, we now believe that the use of NGS has additional benefits." Most, if not all, of the resources cited in the proposed decision memo relied upon germline testing from CLIA-certified or academic laboratories without FDA approval or clearance. Germline testing via CLIA-certified laboratories is appropriate and the standard of care. CMS regulates all laboratory testing (except within research) so prohibiting Medicare coverage of NGS tests that lack FDA-approval is incongruous and will harm patients with germline mutations.

  Recommended Revision: We recommend that CMS eliminate the Food and Drug Administration (FDA) approval or clearance requirement for the diagnostic laboratory test. Alternatively, allow Medicare Administrative Contractors (MACs) to develop local coverage determinations (LCDs) for germline testing of patients with suspected hereditary cancers, including those with breast and ovarian cancer.

• FDA approved or cleared indication for use in that patient's cancer.
  

  The proposed policy states that the diagnostic laboratory test using NGS must have an FDA- approved or -cleared indication for use in that patient's cancer. This suggests that only an FDA-approved or -cleared indication with a companion diagnostic is acceptable. This is unfeasible since there is no NGS test specifically for the detection of germline mutations. As such, the proposed policy fails to provide coverage of germline testing for breast and ovarian cancer.

  As CMS states, the evidence demonstrates that identification of germline mutations guides decision-making and "treatment modalities including chemotherapy, radiotherapy, or surgery" for patients with all stages of cancer. If the lab must have an FDA-approved or -cleared diagnostic test and indication, in essence, CMS is limiting coverage to only those tests with an approved targeted therapy-and again, restricting germline testing to only those patients with recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer.

  Patients make surgical, radiation, and treatment decisions based on their germline test results. Under the proposed policy language, a patient with earlier stage breast or ovarian cancer is not eligible for any NGS-based testing

  Recommended Revision:
  We recommend that CMS eliminate the "FDA approved or cleared therapy for the treatment of breast or ovarian cancer".

• Not been previously tested using NGS.
  In most cases, when tumor profiling identifies a somatic mutation in a cancer susceptibility gene, germline genetic testing is advisable. In addition, even if no potentially inherited mutations are found in somatic testing, this does not preclude the possibility of a hereditary cancer mutation. In "When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing?", the authors note:
  • some tumor testing platforms filter out germline variants to improve the accuracy of somatic variant calls,
  • acquired changes in the tumor-such as large deletions or chromosomal loss-can mask a germline mutation, and
  • not all genes associated with hereditary cancer syndromes are included in somatic test panels.⁴

  NGS tests for use in cancer are often comprised of gene panels that are relevant to certain tumor types. A woman with ovarian cancer who has tumor testing via myChoice, for instance, may learn that she does not carry a BRCA mutation. However, germline testing is still indicated. myChoice does not test for mutations beyond BRCA1/2. In contrast, an NGS-based germline test may identify a mutation in PALB2, ATM, RAD51D, STK11, or one of the Lynch Syndrome mutations, which increase her risk of other hereditary cancers and may change her potential surveillance and treatment plan.

  CMS notes that NGS testing for germline mutations "is an important tool in managing other types of hereditary cancer to reduce mortality and improve other health outcomes for Medicare beneficiaries." NGS has become the standard of care for germline testing. The majority of U.S. labs use this technology, even for "basic" BRCA1/2 testing. Since tumor tests also utilize NGS technology, limiting access to once per lifetime-or once per primary diagnosis-is a flawed approach. This is contrary to national evidence-based guidelines and will result in a significant barrier to appropriate care.

  The Palmetto GBA MolDX LCD on Genetic Testing for Lynch Syndrome recognizes that both germline and somatic testing may be medically necessary in certain circumstances. Its policy supports reflexing to an NGS-based tumor test to germline testing in certain patients.⁵ We support such an approach given the unique value of somatic and germline test results.

  Finally, the patient may have had a prior NGS test outside the field of oncology, such as for a cardiomyopathy.

  Recommended Revision: We strongly urge CMS remove, "The patient has not been previously tested using NGS" requirement. The NCD should allow cancer patients to receive both a somatic and germline NGS-based test when medically appropriate.

• Intersection with existing NCD language.
  It appears that CMS has developed the germline testing policy independent of the prior NCD, but will insert new language into the existing NCD (Appendix B). As just described, the "not been previously tested using NGS" requirement is found in the proposed germline coverage, while somatic testing eligibility requires that the patient has not been previously tested using the same NGS test before. In addition, CMS proposes no change to Section C, which prohibits coverage for patients who do not have advanced cancer (by reference to B.1.). The resulting combination of old and new text is very confusing. Does an NGS-based tumor test bar an individual from accessing NGS-based germline testing? Or, is the policy specific to the use of the NGS diagnostic? For example, a beneficiary who previously had NGS testing for a somatic mutation would not be eligible for coverage of additional tumor tests for the same cancer, but would be entitled to coverage of NGS testing for a germline mutation. The existing format and language creates uncertainty about how to manage patients needing both a somatic and a germline NGS test.

  The focus on a technology (NGS) rather than a test and its purpose may work for some medical or diagnostic technologies, but it is challenging given the varied uses of NGS. Under the current scenario, LCDs enable individuals who undergo germline genetic testing via Sanger sequencing to access tumor testing through the NGS NCD. Conversely, people who have a germline test via NGS technology may fail to qualify for coverage of tumor testing under the proposed language. Many physicians have no knowledge of the lab methods used for genetic tests. This inconsistency will amount to disparate care. Medicare beneficiaries should have equal access to, and coverage of, germline testing regardless of the technology utilized.

  We have asked CMS to clarify that a patient may receive both a somatic and germline NGS-based test when appropriate. However, this is the bare minimum. Cancers and their response to treatment change over time. Patients should have an NGS panel for somatic mutations at the time of diagnosis and again upon progression on additional lines of therapy. Many metastatic patients benefit from repeat tumor testing to adapt treatment appropriately.

  Recommended Revision: As outlined above, we urge CMS to remove, "The patient has not been previously tested using NGS" requirement.

  Another option: CMS can expand the scope of the existing NCD to cover multiple NGS tests in a patient's lifetime, with details left to LCDs. This will facilitate accurate identification of targetable mutations and treatments throughout the progression of one's cancer.

B. MACs and Local Coverage of NGS Testing

Section B of the Proposed Decision Memo gives the MACs authority to develop LCDs for NGS-based germline testing when the patient has:

• a cancer diagnosis other than breast or ovarian cancer,
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer, and
• not been previously tested using NGS.

Given that many germline mutations are associated with risk of more than one cancer, it is reasonable to assume that they convey "risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer." BRCA mutations, for instance, cause increased risk of prostate and pancreatic cancers in addition to breast and ovarian. Like the proposed NGS germline testing policy for those with ovarian or breast cancer, criteria for germline testing of individuals with other cancers is unclear. If a woman is diagnosed with pancreatic cancer and has a family history of ovarian or early-onset breast cancer, is she eligible for NGS-based germline testing under a MAC?

Since there are no FDA-cleared or -approved NGS-based germline tests for breast and ovarian cancer, NGS-based germline testing for breast and ovarian cancer patients appears to be non-covered nationally; and the proposed policy would not permit MACs to cover NGS-based germline tests for these cancers.

Cancers Beyond Breast and Ovarian

The most common germline mutations are associated with Lynch syndrome, affecting approximately 1 in 300 Americans. In light of this, it is unfortunate that CMS did not include colorectal and other cancers associated with Lynch syndrome in its evidence review because studies that assess mortality were lacking. Knowledge of a mutation frequently influences surgical decisions, treatment options, etc. This information also provides physicians with more accurate assessments of cancer risk for other organs, enabling them to tailor health care strategies that may reduce disease-burden and mortality.

While overall survival (OS) is certainly the gold standard in clinical research, numerous factors influence OS including patient demographics, prior therapies, and the total number of lines of therapy. Many strong research studies use progression-free survival (PFS) or time to progression (TTP) as endpoints, especially for rare cancers. PFS is relevant to Medicare beneficiaries with cancer. It is an indication of disease control and stabilization as well as health-related quality of life.^6,7,8,9,10 For patients with germline mutations, the ability to manage morbidity and additional primary cancers is crucial.

It is challenging to have NGS-based germline testing for some cancers (i.e. ovarian and breast) managed at the national level, and others covered under the MACs. We strongly urge CMS to consider giving the MACs authority to develop policies for this testing in all cancer types. Alternatively, the agency should rethink inclusion of these cancers in the proposed NGS germline testing NCD policy:

• Colorectal cancer - Current guidelines suggest genetic evaluation for all newly diagnosed patients with colorectal cancer (alternatively, those diagnosed prior to age 70 years), or based on other criteria such as family history or diagnosis of endometrial cancer before age 60.¹¹ There is considerable stage-independent variability in colorectal cancer outcomes. This inconsistency underscores the need for prognostic and predictive biomarkers to guide therapeutic decision-making. Consequently, many colorectal cancer patients benefit from microsatellite instability testing before the cancer is advanced or metastatic, followed by germline testing as appropriate.

  A deleterious mutation in the MMR (MLH1, MSH2, MSH6, and PMS2) or EPCAM gene is required to diagnose Lynch syndrome. Germline testing should be offered:

  • to patients with microsatellite unstable tumors by MSI/IHC testing;
  • if tumor testing is not feasible and if the clinical suspicion of Lynch syndrome is strong (e.g., individual meets revised Bethesda criteria);
  • if a patient meets the Amsterdam criteria, some experts recommend germline testing without prior tumor testing.¹²

  For those with Lynch syndrome, more extensive colectomy is typically recommended.^13,14 Risk of uterine and ovarian cancer as well as gastric, urinary tract, and small bowel cancer is increased in Lynch syndrome patients. Knowledge of these risks leads to greater patient and provider awareness, which may result in earlier diagnosis of additional primary cancers.

• Prostate cancer - All men with metastatic prostate cancer meet NCCN guidelines for germline genetic testing. In a study of 692 men with metastatic prostate cancer unselected for family history of cancer of age of diagnosis, 11.6% had mutations in one of 16 DNA-repair genes (including 5.3% BRCA2, 1.6% ATM, 1.9% CHEK2, 0.9% BRCA1, 0.4 % RAD51D, 0.4% PALB2).¹⁵ Identification of a germline mutation may have significant diagnostic and therapeutic utility, as demonstrated by the identification of pathogenic germline alterations in men with castration-resistant prostate cancer who respond to PARP inhibition.¹⁶

  Aggressive therapy in early-stage BRCA-positive prostate cancers, particularly those with germline BRCA2 mutations, is indicated. The combination of early radical local treatment (e.g. radical prostatectomy or radiotherapy) with adjuvant systemic therapy is the standard of care for these patients. A 2018 study confirmed that much like BRCA2-related breast and ovarian cancers, men with BRCA2-associated castration-resistant prostate cancers respond better to carboplatin-based chemotherapy than non-BRCA+ prostate cancers.

  There is growing evidence of the presence of germline mutations in men with prostate cancer, and the clinical utility of these findings. A recent study reported in JAMA Oncology by Nicolosi, et al., found that 17% of men with prostate cancer (unselected for stage, age at diagnosis or family history) had germline genetic mutations. BRCA variants accounted for over 30% of the mutations and a number of variants with known therapeutic implications were identified (CHEK2, ATM, PALB2, MUTYH, etc.).¹⁷ Not testing men who meet clinical and family history criteria is a missed opportunity to provide appropriate treatment and to inform increased risk of other cancers.

• Pancreatic cancer - NCCN and ASCO guidelines recommend germline testing for all individuals with pancreatic cancer. A 2018 study of 3030 patients with pancreatic cancer showed that six germline mutations (in the ATM, BRCA2, CHEK2, BRCA1, PALB2, and CDKN2A genes) were seen significantly more frequently in cases than in controls and accounted for 5.5% of the unselected pancreatic cancer patients . The mean age at diagnosis was 65.3, with over 60% of the mutation carriers diagnosed after age 60.¹⁸

  Knowledge of an inherited mutation is increasingly important for pancreatic cancer patients when making treatment decisions because BRCA-associated cancers may respond better to certain treatments, such as PARP inhibitors and/or a regimen that includes oxaliplatin, a platinum-containing drug used in some pancreatic cancer.¹⁹ Results from the POLO clinical trial of the PARP inhibitor olaparib indicate that metastatic pancreatic patients with germline BRCA mutations have significantly longer PFS when treated with maintenance olaparib.²⁰

• Hematologic cancers - As with prior versions of this NCD, hematologic cancers essentially have been excluded from this process due to the "recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer" prerequisite for somatic testing. Lymphoma and leukemia, for instance, do not manifest solid tumors and are staged differently than tumor-based cancers. We request that the NCD be clear on this issue to ensure that Medicare beneficiaries with hematologic diseases have equal access to standard of care tests using NGS technology. We urge CMS to reconsider the wording of the "criteria to qualify for NGS testing" in order to accommodate access to NGS testing for all cancer patients who may benefit.

C. Nationally Non-Covered Services

Section C of the Proposed Decision Memo states, "...NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1." Again, this raises questions about the intersection of the germline policy with the existing NCD language around somatic NGS tests. The proposed germline testing policy does not meet the criteria in B.1. so it appears that the services would not be covered.

The non-covered services section is redundant and unnecessary. Stakeholders have repeatedly expressed concern about this provision as the language may be interpreted to broadly limit NGS testing for diagnostics that do not fall under coverage outlined in the NCD. CMS removed this section in the final NCD released in March 2018, but it reappeared in the version sent to the MACs as a transmittal in November 2018.

Closing Comments

While we appreciate the agency's effort, this policy falls significantly short of providing reasonable and necessary care that aligns with current evidence-based guidelines. Portions of the coverage requirements are vague and overly restrictive. This will lead to confusion and impede access to appropriate diagnostic tests-especially for patients with potentially hereditary breast or ovarian cancer.

The hindrance of patient access to tests that potentially save or prolong life raises concerns. We urge CMS to seriously consider the implications of this NCD and to take the necessary steps to ensure that it does not negatively affect the cancer community by limiting access to care and the potential benefits of precision medicine.

Based on the information provided herein, we recommend that NCD 90.2 undergo significant revisions to eliminate or significantly reduce the coverage restrictions. If germline testing remains a component of this policy, it is important that the NCD title reflect the full scope of its coverage. Given that germline testing has clinical utility beyond advanced cancer, the name should be revised:

National Coverage Determination (NCD90.2): Next Generation Sequencing (NGS) for Treatment and Management of Cancer

If, as we have suggested, CMS decides to exempt NGS-based germline genetic tests from the NCD, the policy can be renamed:

National Coverage Determination (NCD90.2): Next Generation Sequencing (NGS) for Somatic Mutations

Thank you for your time and consideration. We welcome the opportunity to discuss our comments and concerns with CMS staff.

Sincerely,

AliveAndKickn
Alstrom Syndrome International
CancerCare CCARE Lynch Syndrome
Dana-Farber Cancer Institute
Fight Colorectal Cancer
FORCE: Facing Our Risk of Cancer Empowered
Genetic Alliance
HIS Breast Cancer Awareness
Inflammatory Breast Cancer Research Foundation
International Society of Oncology Nurses in Genetics
Li-Fraumeni Syndrome Association
Living Beyond Breast Cancer
Male Breast Cancer Coalition
Metastatic Breast Cancer Alliance
Metastatic Breast Cancer Network
My Gene Counsel
National Ovarian Cancer Coalition
National Patient Advocate Foundation
National Society of Genetic Counselors
No Stomach for Cancer
Ovarian Cancer Research Alliance
Pancreatic Cancer Action Network
Patient Empowerment Network
Prevent Cancer Foundation
Prostate Cancer Foundation
Sharsheret
Stupid Cancer
Triage Cancer
Us TOO International Prostate Cancer Education & Support
Young Survival Coalition

1 Foundation Medicine Expands Indication for FoundationOneRCDx as a Companion Diagnostic for LYNPARZAR (Olaparib), July 1 2019 Press Release (http://investors.foundationmedicine.com/news-releases/news-release-details/foundation-medicine-expands-indication-foundationonercdx)
2 myChoice CDx Technical Information (https://bit.ly/myChoiceCDxSpecs)
3 FDA Evaluation of Automatic Class III Designation for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) (www.accessdata.fda.gov/cdrh_docs/reviews/DEN170058.pdf)
4 DeLeonardis, Kim, et al. "When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing?" Journal of Oncology Practice 2019, 15:9, 465-473https://ascopubs.org/doi/full/10.1200/JOP.19.00201
5 Local Coverage Determination (LCD): MolDX: Genetic Testing for Lynch Syndrome (L35024) (www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35024&ver=50&SearchType=Advanced&CoverageSelection=Local&ArticleType=BC%7cSAD%7cRTC%7cReg&PolicyType=Both&s=48&KeyWord=Lynch+syndrome&KeyWordLookUp=Title&KeyWordSearchType=Exact&kq=true&bc=IAAAACAAAAAA&)
6 Griebsch I, Palmer, et al. "Is progression-free survival associated with a better health-related quality of life in patients with lung cancer? Evidence from two randomised trials with afatinib." BMJ Open 2014;4:e005762. doi: 10.1136/bmjopen-2014-005762 (https://bmjopen.bmj.com/content/4/10/e005762)
7 Kaklamani, VG. "Clinical Implications of the Progression-Free Survival Endpoint for Treatment of Hormone Receptor-Positive Advanced Breast Cancer." Oncologist. 2016 Aug;21(8):922-30. DOI: 10.1634/theoncologist.2015-0366. Epub 2016 Jun 2. (http://theoncologist.alphamedpress.org/content/21/8/922.full)
8 PracticeUpdate Editorial Team. "ABC4 2017: Increased Progression-Free Survival Translates to Slower Decline in Quality of Life in Advanced Breast Cancer." PracticeUpdate, 5 Nov. 2015. (www.practiceupdate.com/content/abc4-2017-increased-progression-free-survival-translates-to-slower-decline-in-quality-of-life-in-advanced-breast-cancer/60477)
9 Sola-Morales, Oriol, et al. "Perspectives to mitigate payer uncertainty in health technology assessment of novel oncology drugs." Journal of Market Access & Health Policy, 2019. 7:1, DOI: 10.1080/20016689.2018.1562861 (www.tandfonline.com/doi/full/10.1080/20016689.2018.1562861)
10 Litton, Jennifer K., et al. "Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation." New England Journal of Medicine, vol. 379, no. 8, 23 Aug. 2018, pp. 753¡V763., doi:10.1056/nejmoa1802905. (www.nejm.org/doi/full/10.1056/NEJMoa1802905)
11 Win, Aung Ko, et. al. "Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer): Clinical Manifestations and Diagnosis." UptoDate. 11 Feb. 2019. (https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis)
12 Win, Aung Ko, et al. "Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer): Clinical Manifestations and Diagnosis." UptoDate. 11 Feb. 2019. (www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis#H72545600)
13 "Lynch Syndrome Factsheet." The Jackson Laboratory, Sept. 2019 (www.jax.org/education-and-learning/clinical-and-continuing-education/cancer-resources/lynch-syndrome)
14 Kawakami, Hisato et al. "Microsatellite instability testing and its role in the management of colorectal cancer." Current treatment options in oncology vol. 16,7 (2015): 30. doi:10.1007/s11864-015-0348-2 (www.ncbi.nlm.nih.gov/pmc/articles/PMC4594190/)
15 Pritchard et al. "Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer." NEJM 2016 August 4; 375(5): 443¡V453. doi:10.1056/NEJMoa1603144.
16 Robinson D, et al. "Integrative clinical genomics of advanced prostate cancer." Cell. 2015; 161:1215¡V28. (www.ncbi.nlm.nih.gov/pubmed/26000489)
17 Nicolosi, Piper, et al. "Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines." JAMA Oncology, vol. 5, no. 4, 2019, p. 523., doi:10.1001/jamaoncol.2018.6760. (https://jamanetwork.com/journals/jamaoncology/fullarticle/2723582?resultClick=1)
18 Hu, Chunling, et al. "Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer." Jama, vol. 319, no. 23, 2018, p. 2401., doi:10.1001/jama.2018.6228. (https://jamanetwork.com/journals/jama/fullarticle/2685154)
19 Kowalewski, Adam, et al. "Emerging Strategies in BRCA-Positive Pancreatic Cancer." Journal of Cancer Research and Clinical Oncology, vol. 144, no. 8, 2018, pp. 1503¡V1507., doi:10.1007/s00432-018-2666-9. (www.ncbi.nlm.nih.gov/pmc/articles/PMC6061050/)
20 Golan et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. NEJM 2019. Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387.

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November 28, 2019

Tamara Syrek-Jensen, JD
Director, Coverage and Analysis Group
Centers of Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Syrek-Jensen,

On behalf of Invitae Corporation, we applaud you and your team at the Centers of Medicare & Medicaid Services (CMS) for reconsidering the National Coverage Determination for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer and for proposing to expand coverage of NGS-based germline diagnostic tests for patients with, or at risk for inherited breast or ovarian cancer. At Invitae, our mission is to make high quality genetic testing part of mainstream medicine by making it more affordable and accessible for everyone who can obtain clinical benefit from this information. By proposing to cover NGS-based germline diagnostic tests for patients with any stage of cancer who are at risk for having an inherited cancer syndrome either through national mandate in the National Coverage Determination (NCD) or through local discretion by the Medicare Administrative Contractors (MACs), Medicare policy aligns with our mission and importantly, CMS is enabling earlier detection of hereditary cancer. We believe the Proposed Decision Memorandum makes great progress from the current version of the NCD in addressing the important benefits that may be obtained from NGS-based germline diagnostic testing for patients at risk for an inherited cancer.

We believe, however, that the Proposed Decision Memorandum, if finalized as written, may inadvertently create a significant gap in coverage for patients at risk for inherited breast or ovarian cancer. In the Proposed Decision Memorandum, it appears CMS is proposing to limit coverage for NGS-based germline diagnostic tests for breast or ovarian cancer to FDA cleared or approved tests? (1). To our knowledge, there are no FDA cleared or approved NGS-based germline diagnostic tests for breast or ovarian cancer (2). This would leave Medicare beneficiaries who are at risk for inherited breast or ovarian cancer with no covered options. It appears coverage of testing for all other types of cancers (“not breast or ovarian cancers”) including laboratory developed tests (LDTs) for these indications are at MAC discretion through the local coverage determination process . We suspect it was not CMS' intent to restrict patient access to these tests by providing no coverage on the national or local level for NGS-based germline tests for breast and ovarian cancer. Therefore, we respectfully recommend that, in the final determination, CMS allow MAC discretion to cover tests performed in a CLIA-certified laboratory for any inherited cancer, including breast or ovarian cancer.

Although the affirmative national coverage in this proposed NCD reconsideration would be limited to breast and ovarian cancer, we firmly believe there should be strong coverage for NGS-based germline testing for all types of hereditary cancers. Fortunately, Invitae is able to offer testing for patients with other hereditary cancers at affordable prices. Under established LCDs today, access to coverage for certain NGS-based germline diagnostic tests has been critical for patient care. It is important that the language chosen for the final NCD does not create a national policy that negates well established local coverage determinations that include hereditary breast and ovarian cancer testing. If LDTs for NGS-based hereditary breast and ovarian cancer coverage are nationally non-covered, hence abrogating existing coverage under well-established LCDs, CMS will significantly reduce patients’ access to germline testing for breast and ovarian cancer, and it will remain unclear as to when tests that meet the coverage criteria would be available. Again, we do not believe this is CMS’ intent. We extend our willingness to help draft simplified, meaningful language, such as in the attachment to this letter.

An additional concern in the Proposed Decision Memorandum is the limitation that the patient has not been previously tested using NGS technology. This is problematic because it limits testing in anyone who has had prior NGS testing for any reason, not just NGS-based germline diagnostic testing for inherited cancer. Under the phrasing of the proposed NCD, a patient would not be eligible for coverage for NGS-based germline diagnostic testing for inherited cancer if the patient previously had any NGS test for any purpose, such as an NGS-based somatic test for targeted mutations to guide therapy of a cancer or even a molecular microbiology test to help diagnose an infection if the molecular method is by NGS. Furthermore, even if the limitation were applied only to NGS-based germline diagnostic testing for inherited cancer, the limitation does not take into account the many cogent reasons why resequencing by NGS for the same indication would be medically reasonable and necessary.

These reasons include:

• the identification of additional genes implicated in causing the condition that were not yet identified and therefore not analyzed in the previous test,
• when the technology available at the time of the previous testing was insufficient to detect clinically relevant mosaic variants or copy number variants, or
• when new reportable pathogenic variants located outside the reportable range of the previous test have been discovered and a repeat test with an expanded reportable range would make it possible to detect these variants.

We urge CMS to correct the imprecise language that refers to all forms of NGS testing in the final determination to limit coverage so as to not preclude medically reasonable and necessary repeat germline testing using gene panels that contain some genetic content that has already been tested in the same Medicare beneficiary if advances in genetic testing indicate that the previous testing was inadequate for the delivery of good patient care.

Thank you for your ongoing engagement with stakeholders on this National Coverage Determination. We appreciate your partnership as we continue to expand access to affordable genetic testing. If we may be of further assistance, please contact Chantelle Schenning at chantelle.schenning@invitae.com or 443-255-1043.

Sincerely,
Sean George
President & Chief Executive Officer
Invitae Corporation

Footnote:
(1) We reach this conclusion because proposed Section B.2 limits national coverage to NGS-based tests that are FDA cleared or approved and which have an indication in the patient’s cancer (which is required to be breast or ovarian cancer), section D leaves to MAC discretion coverage of NGS-based tests solely for cancers other than breast or ovarian cancer, and section C nationally non-covers everything that is not otherwise covered.
(2) We note that Myriad’s BRACAnalysis CDx assay is NOT an NGS-based test: “?BRACAnalysis CDx is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. (see? https://investor.myriad.com/news-releases/news-release-details/myriad-receives-fda-approval-bracanalysis-cdxr-companion). In addition, as a companion diagnostic, the BRCAnalysis test’s FDA-approved claims only relate to the decision to prescribe identified therapeutic compounds, and do not extend to the diagnosis of hereditary breast and ovarian cancer syndromes.

Attachment—Recommended Revision to the Proposed Decision Memorandum

Note: Text that we recommend should be deleted has a strike through and language we recommend be added is denoted in blue font.

Under Section B.2 beginning on page 40 of the memorandum:

2. The diagnostic laboratory test using NGS must have:

• Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostics; and,
• an FDA-approved or -cleared indication for use in that patient’s cancer; and,
• results provided to the treating physician for management of the patient using a report template to specify treatment options.

Effective for services performed on or after ?[Month/XX] [Day/XX], [20XX]?, the CMS, proposes that NGS as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

The patient has:

• ovarian or breast cancer;
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer breast or ovarian cancer; and
• not been previously tested using NGS?-?based germline diagnostic testing for the same type of inherited cancer unless
  • There is established clinical utility present in the remaining, non-duplicative genetic components of the repeat test.
  • The older NGS data was of insufficiently consistent quality to call mosaicism or copy number variants; therefore, resequencing of previously tested genes will be the technically superior and most economical way to detect mosaicism or CNVs.
  • The previous NGS test did not include critical regions of the gene in its reportable range and, therefore, the identification of pathogenic variants with clinical utility outside the reportable range of the older test would justify prompt resequencing of the gene.

The diagnostic laboratory test using NGS must have all of the following:

• FDA approval or clearance;
• an FDA approved or cleared indication for use in that patient’s cancer; and
• results provided to the treating physician for management of the patient using a report template to specify treatment options.

D. Other

Effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of other NGS as a diagnostic laboratory test for patients with cancer only when the test is performed in a CLIA-certified laboratory, ordered by a treating physician, and the patient has:

• either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and,
• either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test was performed only when a new primary cancer diagnosis is made by the treating physician; and,
• decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

Effective for services performed on or after [Month/XX] [Day/XX], [20XX] , Medicare Administrative Contractors (MACs) may determine coverage of other Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when all the following conditions are met:

The patient has:

• a cancer diagnosis other than breast or ovarian cancer,
• clinical indications for germline (inherited) testing,
• risk factors for germline (inherited) cancer other than inherited breast and ovarian cancer, and
• not been previously tested using NGS-based germline diagnostic testing for the same type of inherited cancer unless
  • There is established clinical utility present in the remaining, non-duplicative genetic components of the repeat test.
  • The older NGS data was of insufficiently consistent quality to call mosaicism or copy number variants; therefore, resequencing of previously tested genes will be the technically superior and most economical way to detect mosaicism or CNVs.
  • The previous NGS test did not include critical regions of the gene in its reportable range and, therefore, the identification of pathogenic variants with clinical utility outside the reportable range of the older test would justify prompt resequencing of the gene.

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: National Coverage Analysis (Reconsideration) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen:

On behalf of Foundation Medicine, Inc. (“FMI”), the developer of the FoundationOne®CDx comprehensive genomic profiling test, I am submitting comments on the proposed memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R). We strongly support the Decision Memorandum for NGS for Medicare Beneficiaries with Advanced Cancer issued on March 16, 2018 to provide national coverage for Food and Drug Administration (FDA)-cleared or approved companion diagnostics performed on an NGS platform for their FDA-labeled intended use in beneficiaries meeting the patient clinical criteria.

FMI supports the agency’s decision to maintain coverage of NGS-based tests for Medicare patients with advanced cancer under the original NCD. However, we do request a clarification in the Decision Memo of the revised non-coverage language currently included at Appendix B of the Proposed Decision Memo. Specifically, the non-coverage language in Section C of the proposed chapter 90.2 of the Manual still reads in a way that would non-cover tests where patients do not meet the criteria for the existing NCD. This, of course, contradicts the expanded coverage of NGS-based germline tests that CMS has proposed under this reconsideration.

With regard to the proposed coverage of NGS tests of germline mutations to identify those with inherited cancer who may benefit from targeted treatments based on results of the test, FMI continues to support such coverage.

As previously addressed in our initial public comments submitted on May 28, 2019, we would like to request that CMS use this opportunity to provide clarification related to the coverage of patients in two specific scenarios:

1. Hematologic malignancies-For purposes of determining coverage, can CMS confirm that patients with hematologic malignancies are equivalent to having “metastatic” disease at the time of their diagnosis?


2. CNS malignancies-CNS malignancies are not generally staged, but are instead graded, so the clinical descriptors provided in the NCD do not fully define the applicable clinical scenarios. For purposes of determining coverage, can CMS confirm that patients with CNS malignancies are equivalent to advanced Stage III or IV cancer?

The patient criteria in the NCD (1.a) can also be updated to read, “Patient has any hematologic, or CNS malignancy, or any other recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer to address the above-stated scenarios.

Furthermore, we request that the patient criteria 1.b in the NCD (“Patient has either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician”) be modified to allow for repeat testing upon disease progression on targeted therapy. There are now several studies demonstrating the development of resistance mutations in tumors as a result of being treated with targeted therapy. These resistance mutations are the result of tumor evolution and are not present in the tumor at the time of initial testing. Specific therapies have been FDA-approved in subsequent lines of therapy to address this phenomenon (e.g. osimertinib is used to treat tumors that acquire the T790M alteration in the EGFR gene).

Finally, we applaud CMS for being proactive and visionary in creating an NCD that provides a pathway for coverage of NGS testing for advanced cancer patients. Through this NCD, we believe CMS acknowledged that well-validated NGS-based companion diagnostics is a reasonable and necessary part of cancer care. We firmly believe that it is in the best interest of patients to have access to comprehensive genomic testing that is analytically and clinically validated using the highest standards, particularly when they are being used to help guide therapy selection for patients with advanced cancer. Therefore, we continue to urge CMS to ensure that NGS tests covered for eligible Medicare beneficiaries are well validated, including requiring rigorous evidentiary standards to Medicare Administrative Contractors that have coverage discretion under this NCD.

Please contact Ingrid Marino at 1-952-250-4567 (or by e-mail at imarino@foundationmedicine.com) if you have any questions regarding these comments.

Sincerely yours,

Brian M. Alexander, MD, MPH
Chief Medical Officer
Foundation Medicine, Inc.

References
1. Ahronian L and Corcoran R. Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy. Genome Medicine. 2017;9:37.
2. Kakadia S, Yarlagadda N, Awad R, et al. Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma. OncoTargets and Therapy. 2018;11:7095–7107.
3. Zhang H, Savage S, Schultz AR, et al. Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nature Communications. 2019;10(244) https://doi.org/10.1038/s41467-018-08263-x.
4. McKay R, Werner L, Mostaghel E, et al. A phase II trial of abiraterone combined with dutasteride for men with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2017 February 15; 23(4): 935–945.
5. Pietrantonio F, Vernieri C, Siravegna G, et al. Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. Clin Cancer Res. 2016; 23(10): 2414–22.
6. Gornstein E, Sandefur S, Chung J, et al. BRCA2 reversion mutation associated with acquired resistance to olaparib in estrogen receptor-positive breast cancer detected by genomic profiling of tissue and liquid biopsy. Clinical Breast Cancer. 2017;18(2):184-8.
7. Kondrashova O, Nguyen M, Shield-Artin K, et al. Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 2017; 7(9): 984–998.
8. Wang Z-F, Ren S-X, Li W, and Gao G-H. Frequency of the acquired resistant mutation T790M in non-small cell lung cancer patients with active exon 19Del and exon 21 L858R: a systematic review and meta-analysis. BMC Cancer. 2018;18:148.

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The American College of Medical Genetics and Genomics (ACMG) welcomes the opportunity to comment on CMS’s Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. ACMG is the only nationally recognized professional membership organization dedicated to improving health through the practice of medical genetics and genomics. Our membership includes over 2300 genetics professionals, nearly 80% of whom are board-certified clinical and laboratory geneticists and genetic counselors.

ACMG appreciates CMS’s attention to the importance of germline genetic testing in patients diagnosed with cancer. Recognition and coverage of this type of testing is a key step towards ensuring that Medicare beneficiaries benefit from the concepts of precision medicine. However, we are concerned about certain gaps in the proposed policy and believe that addressing these gaps will lead to better health outcomes for Medicare beneficiaries.

As written, the proposed coverage policy would only apply to germline variant tests for breast and ovarian cancer if they are FDA-cleared or approved NGS-based tests. The local coverage option provided to Medicare Administrative Contractors (MACs) would include laboratory-developed tests (LDTs) but only for cancers other than breast or ovarian. To our knowledge, FDA-cleared or approved NGS-based diagnostic tests for germline variants in breast or ovarian cancer currently do not exist. Current FDA-cleared or approved tests for breast and ovarian cancer are either intended for somatic cells or rely on other methods such as polymerase chain reaction (PCR). To date, NGS-based germline variant tests for breast and ovarian cancers are only offered as LDTs, yet neither the proposed national coverage policy nor the local coverage option provided to MACs would cover these tests.

At minimum, MACs should have the discretion to cover LDTs for inherited breast and ovarian cancer. This could be achieved by revising the local coverage option so that it applies to any cancer diagnosis and is not limited to a “cancer diagnosis other than breast or ovarian cancer”. However, consideration should also be given to a national coverage policy that includes certain LDTs. LDTs are legally marketed tests, and standard of care relies on these tests. Since passage of the Medical Devices Amendments of 1976, the FDA states they have authority to regulate but have opted to use enforcement discretion for the majority of LDTs. Laboratory use of these tests is regulated by CMS as high-complexity tests through the Clinical Laboratory Improvement Amendments (CLIA) program to “ensure the accuracy and reliability of patient test results” (MLN Fact Sheet, ICN 006270 October 2018). It is unclear why such medically relevant tests would not be nationally covered when CMS is ensuring that the results are accurate and reliable, and the tests are legally marketed.

Overall, the proposed coverage policy for breast and ovarian cancer patients is written in such a way that no tests would actually be covered by the policy, and no patients will benefit from it. We appreciate that CMS is acknowledging the benefits of germline testing and are confident that CMS intends to develop coverage policies that will allow Medicare beneficiaries to benefit from such testing. All legally-marketed NGS-based diagnostic tests, including LDTs, that are performed in a CLIA-certified laboratory and intended to detect germline variants in breast and ovarian cancer patients should be covered.

Further, the clinical utility of germline variant identification is not affected by the type of sequencing or genotyping technology that is used. Variant information identified by any analytically and clinically valid test provides the same information that may influence patient management and treatment. In section VII.B.5. (Evidence-Based Guidelines) of the proposed decision memo, CMS notes that guidelines demonstrating clinical utility using non-NGS methods such as PCR or immunohistochemistry (IHC) were not reviewed. It is unclear as to why guidelines discussing the evidence for patient treatment based on germline variant information would be discarded. The significance of a given variant does not change depending on whether NGS, PCR, or other methods were used. Such information is relevant and should not be omitted from the evidence review. Patient access should be based on medical need rather than a specific sequencing or genotyping technology.

Another concern in the proposed decision memo is that both the national policy and local option for germline testing only apply if the patient has “not been previously tested using NGS”. As currently written, this suggests that germline diagnostic testing would not be covered if the patient had any type of prior NGS-based testing, not just NGS-based germline diagnostic testing for inherited cancer or for a specific gene. It is very plausible that a cancer patient may undergo NGS-based somatic and germline variant testing to inform treatment decisions at various stages of disease. Further a patient may have received NGS-based testing for a condition unrelated to cancer, such as to identify another heritable condition or an NGS-based microbial test to diagnose an infection. Even if the policy were reworded to be limited to prior NGS-based germline diagnostic testing for inherited cancer, this still would not account for standard situations in which testing of additional genes is needed or retesting would be warranted. For example, retesting may be needed when new pathogenic variants have been identified that were outside of the original reportable range, and a new test with an expanded reportable range must be performed. We encourage CMS to revise the language to ensure that patient access to medically reasonable and necessary tests is not prohibited by prior testing.

In conclusion, ACMG appreciates the opportunity to provide comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R). We are pleased to see that CMS recognizes the importance of germline variant testing for management and treatment of patients with hereditary cancers, including both those with advanced and nonadvanced disease. We look forward to continuing to work with CMS to ensure that Medicare beneficiaries have access to medically reasonable and necessary genetic tests. For questions or if we can be of further assistance, please contact Michelle McClure at mmcclure@acmg.net.

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November 27, 2019

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore, MD 21244

Re: Coverage of NGS tumor panels CAG-00450R

Dear Ms. Jensen:

The American Cancer Society Cancer Action Network (ACS CAN) appreciates the opportunity to comment on the reopened process for a national coverage decision related to coverage of NGS tumor panels. ACS CAN, the nonprofit, nonpartisan advocacy affiliate of the American Cancer Society, supports evidence-based policy and legislative solutions designed to eliminate cancer as a major health problem. ACS CAN empowers advocates across the country to make their voices heard and influence evidence-based public policy change as well as legislative and regulatory solutions that will reduce the cancer burden.

We commend the Centers for Medicare and Medicaid Services (CMS) for recognizing the restrictions that the previous national coverage determination (NCD) language may have placed on the use of next-generation sequencing (NGS) technology in evaluating germline mutations and we support the proposed expansion of coverage to include germline analysis of breast and ovarian cancer patients. We also support allowing Medicare Administrator Contractors (MACs) to cover non-breast and ovarian cancer germline testing when supported by appropriate evidence.

While the proposed changes with respect to germline testing are welcome, we continue to take issue with several aspects of the NCD that have remained unchanged through several comment periods. Specifically, all versions of the NCD have included language that prohibited MACs from making local coverage determinations (LCDs) for NGS technology in anything other than narrowly defined use cases. This approach continues to indicate a mis-understanding of how the specific NGS test use cases addressed in the NCD fit within the overall landscape of potential uses for NGS technology. As with previous versions of the NCD, CMS is proposing to bar coverage of a wide spectrum of possible future uses of NGS technology without first reviewing evidence for those uses. The narrow reconsideration excluding issues beyond the proposed germline coverage continues to miss an important opportunity to address shortfalls identified in previous comment periods.

Patient restrictions

Two patient restrictions that are part of the NCD continue to be problematic. Specifically, we are concerned with the late-stage requirement and the single testing requirement.

Late stage

The NCD states “…a report of results of a diagnostic laboratory test using NGS … can contribute to predicting a patient’s response to a given drug: good, bad, or none at all.” This is an accurate statement, and importantly its accuracy is not related in any way to the stage of cancer a patient has. As of today, the FDA-approved companion diagnostic claims happen to be in late-stage cancers, but there is no biological or scientific reason that targeted treatments driven by genetic aberrations will not be developed and employed in early-stage cancers. Under the current NCD, such a positive advancement for patients would be barred from coverage, effectively freezing in time the population that can benefit from targeted therapeutic options. Furthermore, the use of the term “stage” is not utilized in the same way in brain cancers or some hematologic malignancies as it is in other solid tumors, so this restriction further adds confusion and is yet another reason to remove reference to staging.

Single testing

Under the current proposal a patient is eligible to be tested only once at a late stage of disease, yet genetic mutations in cancer are dynamic. The proposed NCD seems to assume that new genetic targets would only occur with a new diagnosis; however, the science is clear that treatment itself can place selective pressure on a tumor and cause it to evolve and develop new mutations [1]. This means that the genetic makeup of the same tumor may differ over time and the genetic makeup of metastases may differ from the primary tumor. Clinically this may manifest as the development of resistance to treatment. When such a resistance develops, it may be appropriate to retest in order to identify the new genetic makeup of the same tumor. Restricting the patient to one single opportunity for testing would not capture these changes, and we recommend CMS consider the allowance of retesting after a medically appropriate interval or indication such as acquired resistance.

Lastly, NGS may be used for purposes other than initial diagnosis of a cancer. For example, NGS technology may be used to monitoring the presence or absence of cancer burden within a patient by sampling DNA found in bodily fluids. By its very nature, the monitoring function would require periodic testing.

Technical corrections

A number of technical omissions or errors appear to have been made in Appendix B, which contains proposed decision language.

Following Section B.2., new text was inserted reading:

“Effective for services performed on or after [Month/XX] [Day/XX], [20XX], the CMS, proposes that NGS as a diagnostic laboratory test [is reasonable and necessary] when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:”

The words “is reasonable and necessary” seem to have been omitted in this text and we recommend inserting them (see bracketed text above).

The next paragraph describes patient characteristics, but the language regarding previous testing is ambiguous:

• “not been previously tested using NGS.”

NGS is a technology that could be used in hundreds of contexts, so the assumption is that you do not intend to bar the use of a specific NGS test because a patient has ever been tested for any other disease or condition using a separate unrelated NGS-based test. We propose that you amend this requirement replacing the language referenced above with language in use elsewhere in the existing NCD:

• “not been previously tested using the same NGS test for the same [purpose] “

This same drafting error occurs in the new language proposed under Section D as well and we make the same recommendation as above to clarify.

The non-coverage provision (section C) references patient characteristics under Section B.1., but the newly proposed ovarian and breast allowed uses are not under a numbered section. Is the intention to incorporate these new uses under B.1. and B.2.?

Conclusion

On behalf of ACS CAN we would like to reiterate the ask made in our previous comments [2,3] to request the removal of the noncoverage provisions represented in sections C and D of the NCD, both to preserve existing LCDs as well as to allow coverage policies to adapt to the ever-changing scientific and clinical landscape of genetic testing beyond single companion diagnostic testing of late-stage solid tumors. Research is rapidly driving advances in cancer care, and CMS policies should not deny cancer patients access to the fruits of that research because of an artificial block on a large swath of use cases of this emerging technology. CMS has recognized this dynamic scientific environment with respect to MAC flexibility to cover new germline use cases, but has continued to block appropriate new coverage cases in the somatic testing space. If you have any questions, please feel free to contact me or have your staff contact Mark Fleury (mark.fleury@cancer.org ).

Sincerely,

/Filed electronically/
Lisa A. Lacasse, MBA
President
American Cancer Society Cancer Action Network

1- Merlo, L. M. F., Pepper, J. W., Reid, B. J., & Maley, C. C. (2006). Cancer as an evolutionary and ecological process. Nature Reviews Cancer, 6(12), 924–935. https://doi.org/10.1038/nrc2013
2-American Cancer Society Cancer Action Network comments on NGS NCD (January 17, 2018) https://www.fightcancer.org/sites/default/files/National%20Documents/ACSCAN_Comments_NGSPanelTesting_NCD_Final.pdf
3-American Cancer Society Cancer Action Network comments on NGS NCD (May 29, 2018) https://www.fightcancer.org/sites/default/files/ACSCAN_NCD_NGS_GermlineReopen29MayFinal.pdf

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November 25, 2019

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PUBLIC COMMENT
AGENDIA
Agendia is a leading international developer and manufacturer of molecular diagnostic tests. We appreciate the opportunity to comment on NCD CAG-00450R.
CURRENT STATUS OF NCD:
The NCD currently provides national coverage for FDA-approved combination diagnostics with an on-label indication for patients with advanced cancer. As CMS states, “Medicare’s current coverage of NGS is restricted to patients with a metastatic, or recurrent, or relapsed, or refractory, or a stage III or stage IV advanced cancer. As a result of current evidence and our present analysis, we now believe that the use of NGS has additional benefits.” Local coverage (current section D) is also focused on advanced cancer, since current exclusion Section “C” points to advanced cancer defined in Section “B.1.”
PROPOSED ADDITIONS TO NCD:
The new proposal will allow coverage of hereditary risk testing in earlier stage patients, with national coverage for FDA-authorized tests and local coverage for other tests. However, CMS must revise the non-coverage legacy text in Section C, which it did not do in the proposal.
PROBLEM THAT REQUIRES RESOLUTION:
Many stakeholders have pointed out that if the NCD refers to all types of NGS testing, unintended effects will occur. For example, there are now FDA-authorized NGS tests for HIV genotyping and drug resistance. It doesn’t make sense to block use of this NGS test only in early stage cancer patients, among all Medicare beneficiaries. Similarly, there are now FDA-approved and clinically very important uses of some drugs (Herceptin) in non-metastatic breast cancer (adjuvant therapy), based on Her-2-neu testing which is an on-label test for the FMI F1 CDx NGS test.
Agendia directly faces a very similar problem. Our flagship test, Mammaprint™, was one of the first advanced molecular tests ever to be authorized by the FDA, through the de novo process in 2007. Our test has been covered by Medicare since 2009 and is widely endorsed by national and international guidelines and widely covered by US payors. For breast cancer patients in Asia and Europe, we have been able to migrate our Mammaprint test to an NGS platform. We intend to offer this version of the MammaPrint test in the US; however, if there is no change in the NCD, the future NGS version of our test would not be covered in non-advanced patients, which are the indicated population in our FDA labeling and Medicare local coverage.

PROPOSED EDITS TO NCD:
We propose the following edits to the NCD:
Current Section C must be revised to point only to prior coverage B.2, in order to avoid conflict with the newly proposed hereditary testing language.
We suggest:
C. Nationally Non-Covered
Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above ^FOR THE PURPOSES OF COVERAGE UNDER SECTION B.2.
In addition, there should be a closing comment in Section D, Local Coverage, that allows evidence-based exceptions to the advanced cancer section.
We suggest:
Add to bottom of Section D:
^Other uses of NGS testing in patients with cancer, not precluded by Section C, remain at local coverage discretion.
JUSTIFICATION
The proposed edits bring the intention of the old and the new text into alignment. In addition, we believe that the clause we propose adding to Section D brings the NCD into alignment with statute at Section 1862(a), which requires that NCD determinations have to be based only on evidence that has been publicly reviewed. Therefore, topics and clinical areas not reviewed publicly in the NCD should not be non-covered but left to local discretion.

Sincerely,

William Audeh, M.D., MS
Chief Medical Officer
Agendia, Inc.

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November 25, 2019

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

Dear Ms. Syrek Jensen,

The American Clinical Laboratory Association submits these comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Stage Cancer (CAG-00450R).¹ ACLA is a not-for-profit association representing the nation's leading clinical and anatomic pathology laboratories, including national, regional, specialty, end-stage renal disease, and nursing home laboratories. The clinical laboratory industry is at the forefront of precision medicine, driving diagnostic innovation and contributing more than $100 billion to the nation's economy annually. ACLA member companies have a direct stake in ensuring that laboratory testing using NGS technology is available when a Medicare beneficiary's physician has determined that it is necessary for medical management of the beneficiary.

We appreciate that CMS reopened NCD 90.2 in response to the concerns expressed by ACLA and numerous other stakeholders about its scope and coverage, and we are grateful for the Coverage and Analysis Group's willingness to engage in a collaborative dialogue with ACLA members about this coverage decision. However, we are concerned that CMS's proposed coverage decision would be detrimental to Medicare beneficiaries' access to precision diagnostics to guide cancer treatments. CMS should nationally cover a hereditary breast and ovarian cancer test using NGS technology, whether the test is a laboratory-developed test (LDT) or has been cleared or approved by the Food and Drug Administration (FDA). In the alternative, regardless of the type of cancer, Medicare Administrative Contractors (MACs) should retain discretion to cover a germline test using NGS technology or another technology platform when the test is performed in a CLIA-certified laboratory, the test is ordered by a treating physician, and the patient is seeking treatment and weighing medical management options based on germline mutation status. Additionally, we request that the agency remove overly-broad language in the proposed decision memo on coverage for a test using NGS technology when a beneficiary was "previously tested using NGS." The agency also should revise the broad non-coverage language included in the March 2018 version of the NCD to conform with existing and new text. Our suggestions for changes to the language of the NCD are attached.

In the proposed decision memo, CMS refers variously to "NGS as a diagnostic laboratory test" and "NGS testing." NGS alone does not provide a diagnosis, as it is part of the overall testing process that includes data analysis, annotation, and interpretation. NGS is a test methodology for molecular testing, which includes PCR, qPCR, RT-PCR, Sanger sequencing, fluorescence in situ hybridization (FISH), and microarrays. All of these technologies for molecular testing, including NGS, are used in a laboratory process (sometimes interchangeably) to answer specific questions to aid in management of a patient's disease. Next generation sequencing refers to a technology platform whereby an entire human genome, or specific areas of interest, can be sequenced rapidly to detect deletions of DNA, large genomic deletions of exons or whole genes, and rearrangements in genes. An NGS platform can sequence millions of small fragments of DNA simultaneously.

NGS has not entirely taken the place of other sequencing methods. However, for many existing covered assays, including tumor gene expression assays, NGS can be more cost-efficient, allows for simultaneous interrogation of the entire genome, and can be used with samples with low-input DNA. Instead of sequencing a single DNA fragment, an NGS platform extends this sequencing process across millions of fragments in parallel. PCR-based tests, which are limited by smaller targets, usually require multiple tests to cover all loci of interest to identify relevant variants, whereas NGS-based tests can cover larger regions at comparable costs and with superior accuracy. Laboratories use NGS platforms with analytically- and clinically-validated LDTs and with commercially-available kits that are cleared or approved by the FDA.

ACLA supports national Medicare coverage of germline tests using NGS technology for hereditary breast and ovarian cancer. However, we adamantly oppose CMS's proposal to limit national coverage of these tests to those that are FDA-cleared or -approved. Indeed, there are no such tests on the market today, rendering such coverage illusory. In the proposed decision memo, CMS did not articulate any reason for determining that such a test may be covered by Medicare when it has been FDA-cleared or -approved, but not if it is an LDT or an FDA-cleared or -approved test that has been modified. Naturally, the peer-reviewed studies that CMS cites in support of coverage of hereditary breast and ovarian cancer tests using NGS technology did not involve FDA-cleared or -approved tests-since none exist today.

CMS's own statement supports national coverage of germline testing using NGS technology for hereditary breast and ovarian cancer whether the test is an LDT that is validated in a CLIA-certified laboratory or when it is cleared or approved by the FDA: "For validated tests, we find the benefits in health outcomes of NGS testing for germline mutations for certain cancers outweighs the harms associated with testing."² There are multiple ways that laboratories show evidence of an LDT's validity, other than submitting the test to the FDA for review. CLIA includes extensive requirements for laboratories to verify or establish a test's analytical performance characteristics before offering it and reporting patient results based on the test. CLIA regulations require that laboratories that use LDTs, that modify FDA-cleared or -approved tests, or that use a test system for which the manufacturer did not provide performance specifications, must establish the following performance characteristics before reporting patient test results: accuracy, precision, analytical sensitivity, analytical specificity to include interfering substances, reportable range of test results for the test system, reference intervals (normal values), and any other performance characteristic required for test performance.³ CLIA regulations also require a laboratory director to ensure that test methodologies have the capability of providing the quality of results required for patient care, which is the case only when they are clinically relevant for the patient populations being tested (i.e., are clinically valid).⁴ Clinical validity also is ensured by accreditation by an approved third-party accreditation organization such as the College of American Pathologists, whose goals include ensuring that tests are analytically and clinically valid, that there is patient safety and patient access to testing, and that there is innovation and improvement of LDTs.⁵

A germline test using NGS technology is "validated" when it is performed in a CLIA-certified laboratory, whether the test is an LDT or whether it is an FDA-cleared or -approved test. CMS has provided no evidence to the contrary. It should not finalize its proposal to limit national coverage of hereditary breast and ovarian tests using NGS technology to those that are FDA-cleared or -approved; it should nationally cover tests that are LDTs, as well.

In addition to the discretion afforded the MACs to cover certain tests using NGS technology in beneficiaries with advanced stage cancers, the MACs should retain the discretion to cover germline tests using NGS technology in patients with any type and stage of cancer when certain criteria are met-particularly if the agency does not nationally cover hereditary breast and ovarian cancer tests that are LDTs. Allowing the MACs to develop Local Coverage Determinations (LCDs) for germline testing would accommodate technological advances and changes in evidence-based guidelines that would not require serial changes to the NCD itself.

CMS should allow the MACs to continue to use the existing process for issuing LCDs to cover germline mutation tests using NGS technology that a physician uses in medical management of a Medicare beneficiary. The MACs have well-established methods for consulting with laboratories and other stakeholders, reviewing evidence, and ensuring that tests have been properly validated according to published guidelines (when available), and defining the parameters under which a laboratory test will be covered on a jurisdiction-wide basis. Moreover, retaining broad non-coverage language in the NCD would lead to confusing and illogical coverage inconsistencies, as MACs could continue to cover a test using Sanger sequencing but not NGS technology, and a patient who is commercially insured would have access to a broader array of NGS-based testing options than an otherwise identically situated Medicare beneficiary.

MACs have recognized the value of germline testing and have covered it for some indications for several years. For example, as of 2017, every MAC had an LCD that covers BRCA1 and BRCA2 genetic testing for hereditary breast and ovarian cancer, and each was technology-agnostic. In each instance, the patient and the testing had to meet certain criteria to qualify for coverage, but test methodology was not one of the criteria. MAC discretion would maintain beneficiary coverage under such policies, as opposed to the limited proposed NCD language.

A MAC should be permitted to cover germline testing when:

• The test is performed in a CLIA-certified laboratory;
• The test is ordered by a treating physician;
• The beneficiary is seeking treatment and weighing medical management options based on germline mutation status, as recommended by NCCN guidelines and/or relevant evidence-based medical society guidelines.

These criteria serve to ensure that the testing is covered under a Medicare benefit category and is performed pursuant to national evidence-based medical guidelines, such as those developed by organizations such as the American Society for Clinical Oncology, the College of American Pathologists, the Association for Molecular Pathology, the American Society for Clinical Pathology, the American College of Obstetricians and Gynecologists, and the American College of Medical Genetics, as examples.

CMS should remove overly-broad language in the NCD on coverage for a test using NGS in a beneficiary who was "previously tested using NGS." Proposed language describing national coverage for hereditary breast and ovarian tests using NGS technology and MAC discretion to cover other germline tests states that the patient must not have "been previously tested using NGS." Yet it is not uncommon for germline-tested patients already to have undergone somatic NGS testing, and different germline tests may cover different sets of genes.

The NCD's language would have the effect of limiting Medicare coverage for medically necessary laboratory testing in a number of circumstances. For example, a treating physician may order a germline test using NGS technology for a beneficiary with early stage breast cancer who previously was tested for colorectal cancer with a test using NGS technology (whether covered by Medicare or not). Even the Palmetto GBA MolDx LCD on Genetic Testing for Lynch Syndrome (the most common hereditary cause of colorectal cancer) adopts a stepwise testing approach, wherein steps four and five include reflexing to germline testing, which the policy considers reasonable and medically necessary.⁶ Another example is a beneficiary who has had an NGS-based HIV genotyping test or a red blood cell typing test: under this cancer NCD, either of those tests would be a "previous NGS test", and a later test using NGS technology in that same beneficiary with cancer would not be covered.

It would be nonsensical to non-cover a test for a beneficiary because the test uses the same methodology as an entirely different test the beneficiary had previously. Doing so would be analogous to non-covering a test using Sanger sequencing when the beneficiary previously had another unrelated test that used Sanger sequencing, or even non-covering a serum potassium test because the methodology (ion selective electrode) is the same as that used for a sodium test.

An issue that has yet to be resolved is coverage for NGS-based tests for minimal residual disease (MRD). Since the issuance of the final Decision Memo and its implementation, additional evidence has been published on the value of tests using NGS technology in the assessment and treatment of patients with cancer. One recent study shows that MRD assessment using NGS technology predicts overall survival and disease-free survival better than flow cytometry or qPCR analysis.⁷ The most recent NCCN guidelines for multiple myeloma include response criteria that support the use of tests using NGS technology to identify MRD, and they recommend testing for MRD after each treatment stage.⁸ This approach also is discussed in the recommendations of the International Myeloma Working Group.⁹ Recent NCCN guidelines for acute lymphoblastic leukemia (ALL) also reference NGS methods for disease assessment in adults at baseline and following different treatment phases.¹⁰

Repeat testing using NGS technology in patients with multiple myeloma and ALL should not be foreclosed or complicated by language in the existing NCD limiting testing when a patient has been "previously tested using the same NGS test for the same primary diagnosis of cancer," because that is precisely what the evidence-based guidelines call for. Several additional hematologic cancer guidelines also support MRD assessment at relevant points in a patient's cancer care, and it is likely that testing using NGS technology increasingly will be a recommended method for such assessments.¹¹ CMS should ensure that Medicare beneficiaries with hematologic diseases who may benefit from MRD assessment have access to tests using NGS technology, as recommended by evidence-based guidelines, and the text of the NCD should be clear on this issue.

As written, the NCD covers a test using NGS technology in a patient with "recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer." As we have discussed with you in the past, hematologic malignancies are not staged according to a TNM staging system, nor are all hematologic malignancies staged alike. We support the approach to this incongruity that is taken in the Palmetto GBA MolDx draft LCD on Myeloid Malignancies and Suspected Myeloid Malignancies, which classifies these kinds of diseases as refractory and/or metastatic cancers for purposes of Medicare coverage.12 We have suggested changes to the text of the NCD to reflect that a test using NGS technology may be covered by a MAC when used in a patient with a diagnosis with a suspected or diagnosed hematologic malignancy when performed in a CLIA-certified laboratory and ordered by the treating physician.

Thank you for your consideration of ACLA's comments.

Sincerely,

/s/
Julie Khani, President
American Clinical Laboratory Association

A. General

Clinical laboratory diagnostic tests can include tests that, for example, predict the risk associated with one or more genetic variations. In addition, in vitro companion diagnostic laboratory tests provide a report of test results of genetic variations and are essential for the safe and effective use of a corresponding therapeutic product. Next Generation Sequencing (NGS) is one technique that can measure one or more genetic variations as a laboratory diagnostic test technology, such as when used as a companion in vitro diagnostic test.

Patients with cancer can have hereditary, recurrent, relapsed, refractory, metastatic, and/or advanced stages III or IV of cancer. Clinical studies show that genetic variations in a patient's cancer can, in concert with clinical factors, predict how each individual responds to specific treatments.

In application, a report of results of a diagnostic laboratory test using NGS (i.e., information on the cancer's genetic variations) can contribute to predicting a patient's response to a given drug: good, bad, or none at all. Applications of tests using NGS to predict a patient's response to treatment occurs ideally prior to initiation of such treatment.

B. Nationally Covered Indications

Effective for services performed on or after March 16, 2018, the Centers for Medicare & Medicaid Services (CMS) has determined that a test using Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician, and when all of the following requirements are met:

1. Patient has:
   • either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer, including any suspected or diagnosed hematologic malignancy; and,
   • either not been previously tested using the same NGS test for the same primary diagnosis of cancer, or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and,
   • decided to seek further cancer treatment (e.g., therapeutic chemotherapy).
2. The diagnostic laboratory test using NGS must have:
   • Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,
   • an FDA-approved or -cleared indication for use in that patient's cancer; and,
   • results provided to the treating physician for management of the patient using a report template to specify treatment options.

In addition, Eeffective for services performed on or after [Month/XX] [Day/XX], [20XX], the CMS, proposes that CMS has determined that a test using NGS as a diagnostic laboratory test is reasonable and necessary and covered nationally when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

The patient has:

• ovarian or breast cancer;
• clinical indications for germline (inherited) testing, and
• risk factors for germline (inherited) breast cancer or ovarian cancer; and
• not been previously tested using NGS.

The diagnostic laboratory test using NGS must have all of the following:

• FDA approval or clearance;
• an FDA approved or cleared indication for use in that patient's cancer; and

Results must be provided to the treating physician for management of the patient using a report template to specify treatment options.

C. Nationally Non-Covered

Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above.

D. C. Other

Effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of other tests other than those described in Section B using NGS as a diagnostic laboratory test for patients with cancer only when the test is performed in a CLIA-certified laboratory, ordered by a treating physician, and the patient has:

• either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer, including any suspected or diagnosed hematologic malignancy;
• either not been previously tested using the same NGS-based test for the same primary diagnosis of cancer or repeat testing using the same NGS-based test was performed only when a new primary cancer diagnosis is made by the treating physician or to detect minimal residual disease; and
• decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

In addition, Eeffective for services performed on or after [Month/XX] [Day/XX], [20XX], Medicare Administrative Contractors (MACs) may determine coverage of other tests other than those described in Section B using Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when all the following conditions are met:

The patient has:

• the beneficiary has a cancer diagnosis other than breast or ovarian cancer, clinical indications for germline (inherited) testing, and risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer;
• the test is ordered by a treating physician; and
• the beneficiary is seeking treatment and weighing medical management options based on germline mutation status, as recommended by NCCN guidelines and/or relevant evidence-based medical society guidelines.
• not been previously tested using NGS.

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1 The name of the NCD should be changed to reflect that coverage of tests using NGS technology is conferred not only for beneficiaries with advanced cancer, but also for beneficiaries with any stage cancer who receive germline testing under certain conditions.
2 Proposed Decision Memo, Sec. VIII.
3 42 C.F.R. § 493.1253(b)(2).
4 42 C.F.R. § 493.1445(e)(3)(1).
5 Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS), "U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and Human Services (Apr. 2008).
6 Proposed Local Coverage Determination (LCD): MolDX: Genetic Testing for Lynch Syndrome (L35024), available at https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35024&ver=50&SearchType=Advanced&CoverageSelection=Local&ArticleType=BC%7cSAD%7cRTC%7cReg&PolicyType=Both&s=48&KeyWord=Lynch+syndrome&KeyWordLookUp=Title&KeyWordSearchType=Exact&kq=true&bc=IAAAACAAAAAA&.
7 Onecha E et al., A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia. Haematologica. 2019;104(2):288-296.
8 NCCN Clinical Practice Guidelines in Oncology, Multiple Myeloma, Version 2.2019 (Nov. 16, 2019) at MYEL-D 1, 3.
9 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-46.
10 NCCN Clinical Practice Guidelines in Oncology, Acute Lymphoblastic Leukemia, Version 2.2019 (May 15, 2019) at ALL-F.
11 See, e.g., Press, RD et al. NGS-defined minimal residual disease before stem cell transplantation predicts acute myeloid leukemia response. Am J Hematol. 2019 May 23. doi:10.1002/ajh.25514.
12 Proposed Local Coverage Determination: Next Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies (DL38047); available at https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=38046&ver=3&DocID=DL38047&bc=gAAAABAAAAAA&.

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NCA Restriction to Specifically NGS Evidence Doesn’t Match FDA Approach

For Revision 90.2R1 (CASG 00450R), CMS follows the convention established in NCD 90.2 of using primarily, or only, NGS-based evidence. This is not the approach the FDA uses.

** Background

Sequencing tests of different methods are different than imaging tests of different methods. For example, ultrasound of the liver and CT of the liver both may be used to diagnose liver cancer. However, ultrasound produces data based on short frequency sound reflectance, while CT is based on radiographic density, similar to an x-ray. With sequencing tests, different methods (PCR, Sanger, NGS) are used to identify a sequence of interest. When that sequence is identified, the result is the same.

** Concrete Examples

Nowhere is this more clear than in the FDA approval review for the FoundationOne CDx text.¹ In the original approval, used for NCD 90.2, there were seven genetic reports². Nearly all of these were based on concordance of the NGS report sequence with a priori report sequence.

For example,
(1) the BRAF V600 test and the EGFR Exon Deletion reports in the NGS FMI test were not based on new clinical trials and new patient evidence of any kind for the NGS version. Rather, FDA required that in samples of convenience – positive and negative blocks from a repository, not from clinical trials – were shown to match.
(1A) The NGS FMI test for matched the cobas V2 test for EGFR deletions.
(1B) The NGS FMI test matched the cobas V600 ThXID test for BRAF mutations.

These were benchtop studies, where boxes of paraffin blocks were extracted for DNA that was run on both the older (PCR) and newer (NGS) test. There is no new NGS method clinical data. It’s just lab bench accuracy data.

And if you look at the validation of the Cobas test, it was LDT Sanger sequencing. So LDT Sanger sequencing was used to validate the Cobas PCR test which was used to validate the FDA FMI NGS test.

** Other Sequencing Approvals at FDA

This is also true for product categories. While there are SOME FDA product categories like PQP, that are specific for NGS method testing³, there are other FDA sequencing categories that are not specific to test method.⁴

For another example, FDA has one guidance and uses one type of authorized genetic sequence database for human genetic tests, whether Sanger, PCR, or NGS ⁵. These databases can be used for FDA genetic test approval while the databases do not distinguish, nor does FDA, what method was used to get the clinically valid sequence result stored in the database.

** Summary

In summary, FDA does not generally distinguish sharply between NGS and other sequence validity, but builds NGS approvals extensively on the evidence of prior non-NGS sequencing tests.

This NCD Should Only Cover or Non-Cover Topics Explicitly Reviewed

Statute requires that NCDs should only cover or non-cover those topics that the NCD explicitly reviews in the body of the NCA.

CMS follows this approach in most cases (for example, an NCA on cardiac valves only results in an NCD that covers or does not cover cardiac valves.)CMS violates this principle by excessively global exclusionary language.For example, a cancer test NCD should not block coverage of HIV genotyping testing only if it is performed by an FDA approved test and only in stage 1-2 cancer patients.This is surely an inadvertent result and can be avoided by small edits to the NCD.

For example, if an NCD reviews topics A,B, C, the NCD can cover “A,” non-cover “B,” and leave “C” to local discretion. What the NCD cannot do is non-cover E, F, and G.

** Background: Statute at Section 1862

Section 1862 of the Social Security Act is titled “Exclusions from Coverage” and provides instructions on how exclusions from coverage must be made. In short, they must be made carefully and with explicit evidence review and public comment, whether LCDs or NCDs.

Section 4009 of 21st Century Cures amends 1862(l) to require MAC LCDs to include an evidence summary, sources of all evidence, and explanation of rationale. This legislation did not need to make similar requirements for CMS NCDs, because it was already there. Section 1862(a), just prior to (b), states in part:

If a medical field includes topics A,B,C,D,E,F, the evidence for A,B,C cannot support non-coverage of D,E,F. And it is not enough for CMS staff to” consider” the evidence – for example, driving over to National Library of Medicine, looking at some articles, but keeping no written notes and writing no NCA text for the public. The statute requires that the evidence be “in the determination” and “available to the public” with clear statements and rationales. Statute is focused on what the public sees. Therefore, blanket statements like “No other clinical chemistry testing” or “no other biological testing” or “no other NGS testing” should be avoided. Because this is based on statute, the NCD should be revised accordingly in the 450R process.

NCD 90.2
Revision 1 (CAG 00450R)
NGS Testing in Cancer Patients

Bruce Quinn MD PhD
Los Angeles, CA
bruce@brucequiinn.com 323 839 8637

Note:
I have worked on CMS coverage policy full time for 15 years, and I have worked with a number of companies and associations to help them understand and comment on this NGS NCD. Clients includes those who perform FDA and LDT tumor testing, germline testing, serial testing (e.g. MRD), and who are migrating covered tests onto NGS platforms. However, this analysis and rationale is my own.
Submitted by email as PDF: CAGinquiries@cms.hhs.gov

1. Title Correction
Recommendation	Purpose	Comment
Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer ^ for Treatment and Management of Cancer.	Match title to new and old content	Delete "Medicare beneficiaries". this is never normally found in Medicare LCD titles. Delete "With Advanced Cancer". does not fit content now. Insert "For Treatment and Management of Cancer'

2. Correct Exclusionary Language in NEW Text
Recommendation	Purpose	Comment
Not been tested previously using NGS. ^Not been tested previously for the same germline gene or genes using NGS.	Make the exclusionary bullet logical. Match text to a logical intent. This language occurs in two proposed positions; same fix in both places.	Prior text over-reached to encompass ANY form of NGS testing . for example, even HIV genotyping, or even NGS testing for a rare cardiomyopathy. This doesn't make sense.

3. Clarity
Recommendation	Purpose	Comment
Explain the difference intended for these two bullets: ** clinical indications for germline (inherited) testing, ** risk factors for germline (inherited) cancer breast or ovarian cancer; and	Either explain in body of final NCA or revise the NCD text.	Consider, in this order: Bullet #1 - Risk factors for germline (inherited) breast or ovarian cancer; and Bullet #2 . ^ Clinical indications for change in management based on results of testing;

4. Wording of Proposed MAC Testing
Recommendation	Purpose	Comment
Effective for services performed on or after (Month Day Year) Medicare Administrative Contractors (MACs) may determine coverage of other Next Generation Sequencing (NGS) as a diagnostic laboratory test when c. all the following conditions are met: The patient has: * a cancer diagnosis other than breast or ovarian cancer, * clinical indications for germline (inherited) testing, * risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer, and * not been previously tested using NGS.	Either explain in body of NCA or revise text. I believe numerous parties suggest this change to bring the NCD into alignment with actual FDA products. Note, consider also changes for clarity in Suggestion #3 above.	CMS wants to assure coverage of breast and ovarian germline tests in the future, as they are created. I believe CMS is reluctant to give NCD coverage for LDT tests which would force coverage of any LDT from anyone, whether they meet for example MolDx criteria or not. The suggested strikeout will ensure access to medically necessary tests that meet MAC criteria. Note that the coverage is conditional on downstream MAC decisions (MACs "MAY" determine coverage).

5. Correctly target original section "C"
Recommendation	Purpose	Comment
C. Nationally Non-Covered Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above ^for the purposes of national coverage under section B.2.	Harmonize old and new parts of the LCD. This edit is also part of a double edit proposed in Section 6, next.	CMS proposed no change to section "C". However, as CMS states explicitly, the old NCD limited testing only to advanced cancers. In the proposed full new NCD, as shown in Appendix, "C" appears to inadvertently apply to new coverage of germline testing, which was not intended as shown in body of NCA. Insert phrase as shown, to target the coverage restriction to the sections B1 and B2, where "C" originally applied.

6. ENSURE THAT ANY NON-COVERAGE STATEMENTS ARE RATIONAL, BASED ON PUBLIC EVIDENCE, AND JUSTIFIED.
>> Note, this recommendation includes Recommendation 5.
Recommendation
C. Nationally Non-Covered Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above ^for the purposes of national coverage under section B.2. D. Other Effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of other NGS as a diagnostic laboratory test for patients with cancer only when the test is performed in a CLIA-certified laboratory, ordered by a treating physician, and the patient has: either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and, either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test was performed only when a new primary cancer diagnosis is made by the treating physician; and, decided to seek further cancer treatment (e.g., therapeutic chemotherapy). Effective for services performed [on or after Month Day Year], Medicare Administrative Contractors (MACs) may determine coverage of other Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when all the following conditions are met: The patient has: a cancer diagnosis other than breast or ovarian cancer, clinical indications for germline (inherited) testing, risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer, and not been previously tested using NGS. ^Other uses of NGS testing in patients with cancer, not precluded by Section C, remain at local coverage discretion.
Additions to the SSA at 1862 by the 21st Century Cures Act require that MAC LCDs must list and discuss all evidence and rationale for the public. 21st Century Cures Act did not need to add this language for NCDs, because this public display of all evidence and rationale was already required by SSA at 1862 (text immediately preceding (1862(b)).) Congress instructs the NCD authors as follows: "In making a national coverage determination the Secretary shall ensure in the determination, provide a clear statement of the basis for the determination (including responses to comments received from the public), the assumptions underlying that basis, and make available to the public the data (other than proprietary data) considered in making the determination." Uses of NGS testing have rapidly changed. For example: NGS testing for HIV genotyping has passed FDA review (Sentosa SQ HIV Genotyping Assay; BR190330). Prognostic tests like Agendia Mammaprint are widely covered by US insurers, endorsed in guidelines, and used internationally, while migrating to NGS platforms in other countries. Migration to NGS platform with FDA approval should not inadvertently cause non-coverage. The FMI Foundation One CDx test now already has at least one major FDA on label use (drug Herceptin based on gene Her2neu) which is focused on Stage 2, non-metastatic breast cancers. Thus, a major FDA cancer drug used in non-metastatic patients is already today on label for an NGS test. It does not make sense for the NCD to non-cover these applications with no review of them. It is almost like an NCD for heart valves carefully reviewing cardiac valves, but then in closing state that other cardiac devices such as cardiac pacemakers are not covered. It wouldn't be sensible, and it wouldn't meet the statutory instruction that all parts of the decision have a clear rationale including stated assumptions and the evidence data used for that part of the decision. By adding a sentence, "^Other uses of NGS testing in patients with cancer, not precluded by Section C, remain at local coverage discretion" the NCD makes more sense and comes into alignment with the statute 1862 demanding that only covered (B) and non covered (C) decisions that are based on stated and reviewed evidence are includable in an NCD. Can CMS make this edit in 450R? Yes. The edit is permissible. Even though CMS did not discuss revision of exclusionary language in the original scope, this edit is required to (A) bring the different parts of the NCD into harmony and (B) bring the NCD as a whole into alignment with statute 1862 as quoted.

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1 https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019B.pdf
2 https://brucedocumentblog.blogspot.com/2018/01/informally-summaryg-fmi-cdx-concordance.html
3 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm?id=5093
4 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=866.5940
5 https://www.fda.gov/media/99200/download

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November 22, 2019

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R)

Dear Ms. Jensen,

The American College of Obstetricians and Gynecologists (ACOG), representing more than 58,000 physicians and partners in women's health, appreciates the opportunity to provide comments on the proposed decision memo for NGS for patients with cancer. As physicians dedicated to providing quality care to women, ACOG appreciates the efforts CMS is taking to expand coverage and allow NGS for patients with ovarian or breast cancer.

As noted in the support text for the proposed decision memo, Section A: What is Cancer?, ACOG clinical guidance recommends that genetic testing be offered to women affected with cancer and women unaffected with cancer but may have an increased likelihood of having an inherited predisposition to breast, ovarian, tubal or peritoneal cancer. The proposed decision memo closely supports ACOG's clinical guidance by including clinical indications and risk factors for inherited testing. However, the policy as written requires that all the listed criteria are present, which limits the genetic testing to only those women with diagnosis of ovarian or breast cancer.

As acknowledged in the memo, knowing the origins of cancer does direct the course of treatment. However, it is equally or more important to identify genetic markers for the early identification of cancer. Ovarian cancer lacks an effective screening test and presents with no distinct symptoms in the early stages. According to the National Academies of Sciences, Engineering and Medicine consensus study report on ovarian cancers,¹ about two-thirds of women diagnosed with ovarian cancer present in the advanced stage of the cancer, and less than 30 percent survive past 5 years. Additionally, BRCA1 and BRCA2 genes associated with breast cancer are also associated with ovarian cancer. Therefore, it is essential that women not yet diagnosed with cancer should be eligible for NGS testing when they also meet the risk factors as stated in the ACOG clinical guidance² noted in the proposed memo, and consistent with the ACOG Committee Opinion No. 727: Cascade Testing: Testing Women for Known Hereditary Genetic Mutations Associated with Cancer.³

Therefore, ACOG requests the following changes:

• Change the title of the policy to read Next Generation Sequencing (NGS) for Medicare Beneficiaries at Risk of Inherited Ovarian or Breast with Advanced Cancer
• Change the requirements of the patient to read: The patient has not been previously tested using NGS and has:
  • ovarian or breast cancer; OR
  • clinical indications for germline (inherited testing); and
  • risk factors for germline (inherited) breast or ovarian cancer.

Thank you for the opportunity to provide comments on the proposed memo. Should you have any questions regarding our comments, please contact Lisa Satterfield, Senior Director of Health Economics & Practice Management, at lsatterfield@acog.org or 202-558-3219.

Sincerely,

Maureen G. Phipps, MD, MPH, FACOG
Chief Executive Officer

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1 National Academies of Sciences, Engineering, and Medicine. 2016. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press. https://doi.org/10.17226/21841.
2 Hereditary breast and ovarian cancer syndrome. Practice Bulletin No. 182. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017:130:e110-V26.
3 ACOG Committee Opinion No. 727: Cascade Testing: Testing Women for Known Hereditary Genetic Mutations Associated With Cancer. Committee on Gynecologic Practice. Obstet Gynecol. 2018 Jan;131(1):e31-e34. doi: 10.1097/AOG.0000000000002457.

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November 18, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: CAG-00450R

Dear Ms. Syrek Jensen,

On behalf of Illumina, a leading developer and manufacturer of next generation sequencing (NGS) tools for both research and clinical use, we appreciate the opportunity to provide comments on the Proposed National Coverage Determination for Diagnostic Laboratory Tests using Next Generation Sequencing (NGS) for Medicare Beneficiaries with Germline (Inherited) Cancer.

First, we would like to commend the Centers for Medicare & Medicaid Services (CMS) and the U.S. Food and Drug Administration (FDA) for their efforts and leadership in expanding the current NCD 90.2 on Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer to include germline testing for any cancer stage for breast and ovarian cancer. In addition, we appreciate that this step provides a path forward for future FDA germline approved tests beyond companion diagnostics, and allows MACs to consider lab developed germline tests for cancers other than breast and ovarian.

While we are fully supportive of germline testing for breast and ovarian cancer patients when clinically indicated as outlined in the revised NCD, we feel strongly that some revisions are necessary to ensure that Medicare beneficiaries will be able to benefit from the proposed changes.

Patient Access Considerations

• Currently there are no FDA approved germline NGS tests for breast or ovarian cancer

  There are currently no FDA-approved or FDA-cleared NGS-based tests on the market for germline breast or ovarian cancer. In addition, because the proposed guideline allows MACs to only consider coverage for germline cancer tests other than breast and ovarian, this policy would eliminate any coverage at all for those determined most likely to benefit.

• The ‘not been previously tested using NGS’ criteria may inappropriately eliminate appropriate patients from coverage

  NGS is a technology platform, and as such, is the basis for a wide range of tests including, but not limited to¹:

  • Immune deficiency syndromes
  • Connective tissue disorders
  • Cardiomyopathies
  • HLA Typing
  • Microbial Analysis
  • RNA sequencing and expression
  • Minimal Residual Disease

  It is entirely plausible that a Medicare beneficiary could have an appropriate NGS test for a different clinical indication, and therefore be non-covered for germline breast and ovarian cancer because the current coverage criteria explicitly states, “no prior NGS test.”

• The Risk Factors section in the Background are by the American College of Obstetricians and Gynecologists (ACOG), which serves only women, and doesn’t address germline testing in men with breast cancer.
Recommendations
• We recommend that sections A and B of the Decision Memo be revised in the following manner, as noted below. These changes are minimal and would allow Medicare members to have immediate access to NGS tests for breast and ovarian cancer.

  1. The Centers for Medicare & Medicaid Services (CMS) proposes that the evidence is sufficient to expand coverage of Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:
     The patient has:
     • ovarian or breast cancer;
     • clinical indications for germline (inherited) testing,
     • risk factors for germline (inherited) breast or ovarian cancer; and
     • not been previously tested using NGS.not been previously tested using the same NGS test for a germline indication for the same primary diagnosis of cancer
     The diagnostic laboratory test using NGS must have all of the following:
     • Food and Drug Administration (FDA) approval or clearance;
     • an FDA approved or cleared indication for use in that patient’s cancer; and
     • results provided to the treating physician for management of the patient using a report template to specify treatment options.
  2. Other
     Medicare Administrative Contractors (MACs) may determine coverage of other Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when all the following conditions are met:
     The patient has:
     • a cancer diagnosis
     • clinical indications for germline (inherited) testing,
     • risk factors for germline (inherited) cancer other than inherited breast or ovarian cancer, and
     • not been previously tested using the same NGS test for a germline indication for the same primary diagnosis of cancer
  3. We further recommend modifying the Risk Factors Section of the Background section A to include men with breast cancer. After the section for women from ACOG, the following information could be added:
     Male breast cancer is rare, accounting for < 1% of all cancers in men. A family history consistent with hereditary breast and ovarian cancer (HBOC) is found in 15-20% of men with breast cancer, and 10% of affected men have a BRCA2 mutation². In a joint statement reaffirmed in 2019, the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC), recommends that all men with breast cancer be referred for genetic counseling and testing for HBOC^3,4.

Thank you for the opportunity to comment on this NCD revision. Furthermore, we welcome the opportunity to work with CMS in helping to establish and evaluate NGS-based applications for Medicare patients.

Sincerely,

Ammar Qadan
Vice President, Global Market Access
Clinical Genomics
Illumina, Inc.

References:

1. Yohe S, Thyagarajan B. Review of Clinical Next-Generation Sequencing. Arch Pathol Lab Med. 2017 Nov;141(11):1544-1557
2. Cardoso F, Bartlett JMS, Slaets L, et al. Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Ann Oncol. 2018;29(2):405–417.
3. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015 Jan;17(1):70-87
4. Bashford MT, Kohlman W, Everett J, Parrott A, Pollin TI; Practice Guidelines Committee of the National Society of Genetic Counselors and the Professional Practice and Guidelines Committee of the American College of Medical Genetics and Genomics. Addendum: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2019 Jul 23

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